US20120277155A1 - Therapy for kidney disease and/or heart failure - Google Patents

Therapy for kidney disease and/or heart failure Download PDF

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Publication number
US20120277155A1
US20120277155A1 US13/368,285 US201213368285A US2012277155A1 US 20120277155 A1 US20120277155 A1 US 20120277155A1 US 201213368285 A US201213368285 A US 201213368285A US 2012277155 A1 US2012277155 A1 US 2012277155A1
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Prior art keywords
natriuretic peptide
peptide
subject
infusion
drug
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William P. VanAntwerp
Andrew J. L. Walsh
VenKatesh R. Manda
John Burnes
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Capricor Therapeutics Inc
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Medtronic Inc
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Priority to US13/368,285 priority Critical patent/US20120277155A1/en
Assigned to MEDTRONIC, INC. reassignment MEDTRONIC, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: VAN ANTWERP, WILLIAM P., MANDA, VENKATESH R., BURNES, JOHN, WALSH, ANDREW J.L.
Publication of US20120277155A1 publication Critical patent/US20120277155A1/en
Assigned to CAPRICOR THERAPEUTICS, INC. reassignment CAPRICOR THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MEDTRONIC, INC.
Priority to US14/555,016 priority patent/US9616107B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2242—Atrial natriuretic factor complex: Atriopeptins, atrial natriuretic protein [ANP]; Cardionatrin, Cardiodilatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142—Pressure infusion, e.g. using pumps
    • A61M5/14212—Pumping with an aspiration and an expulsion action
    • A61M5/14228—Pumping with an aspiration and an expulsion action with linear peristaltic action, i.e. comprising at least three pressurising members or a helical member
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142—Pressure infusion, e.g. using pumps
    • A61M5/14244—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • A61M5/14276—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body specially adapted for implantation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the invention relates to therapies involving the administration of a natriuretic peptide for the treatment of pathological conditions such as kidney disease alone, heart failure alone, or kidney disease with concomitant heart failure.
  • the systems and methods of the invention can increase and/or control in vivo levels of natriuretic peptide in the plasma or serum of the subject to optimize the outcome of a therapeutic regimen(s).
  • the invention further relates to the field of chronic and acute delivery of a drug through routes of administration including but not limited to subcutaneous, intravascular, intraperitoneal and direct to organ. A preferred route is subcutaneous administration.
  • the methods of delivery contemplated by the invention include, but are not limited to, implanted and external pumps at programmed or fixed rates, implanted or percutaneous vascular access ports, depot injection, direct delivery catheter systems, and local controlled release technology.
  • Kidney disease also known as renal disease, is a progressive loss in renal function over a period of months or years.
  • Kidney Disease (KD) is a major U.S. public health concern with recent estimates suggesting that more than 26 million adults in the U.S. have the disease including chronic kidney disease (CKD).
  • the primary causes of KD are diabetes and high blood pressure, which are responsible for up to two-thirds of the cases.
  • CKD chronic kidney disease
  • the prevalence of KD has increased due to a rising incidence of diabetes mellitus, hypertension (high blood pressure) and obesity, and also due to an aging population. Because KD is co-morbid with cardiovascular disease, heart failure is a closely related health problem.
  • CKD Chronic Kidney Disease
  • patients have an increased risk of death from cardiovascular events because CKD is thought to accelerate the development of heart disease (McCullough et al., Chronic kidney diseases, prevalence of premature cardiovascular disease, and relationship to short-term mortality, Am. Heart J., 2008; 156:277-283).
  • CKD patients generally have cardiac-specific mortality rates many times higher than age- and sex-matched non-CKD populations, and it has been suggested that the pathological heart-kidney interactions are bidirectional in nature (Ronco C. et al., Cardiorenal syndrome, J. Am. Coll. Cardiol. 2008; 52:1527-39).
  • Type II Cardio-Renal Syndrome is expressly defined as constituting chronic abnormalities in cardiac function (e.g., chronic congestive heart failure) that simultaneously causes progressive and permanent kidney disease.
  • Type IV CRS is defined under the same classification scheme as being a type of kidney disease that contributes to decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse cardiovascular events.
  • HF Heart failure
  • ADHF acute decompensated
  • HF is a common condition that affects approximately 5 million people in the United States, with 550,000 new cases diagnosed each year. Symptoms of HF include swelling and fluid build-up in the legs, feet, and/or lungs; shortness of breath; coughing; elevated heart rate; change in appetite; and fatigue. If left untreated, compensated HF can deteriorate to a point where a person undergoes ADHF, which is the functional deterioration of HF.
  • ADHF is a major clinical challenge because HF as a primary discharge diagnosis accounts for over 1 million hospital discharges and over 6.5 million hospital days (Kozak et al., National Hospital Discharge Survey: 2002 annual summary with detailed diagnosis and procedure data, Vital Health Stat. 13, 2005; 158:1-199).
  • the financial burden due to HF is largely borne by public health resources (e.g., Medicare and Medicaid) wherein the 6 month readmission rate is 50%, the short-term mortality rate (i.e., 60-90 days) is around 10%, and the 1 year mortality risk is around 30% (Jong et al., Prognosis and determinants of survival in patients newly hospitalized for heart failure: a population based study, Arch. Intern. Med. 2002; 162:1689-94).
  • ADHF Alzheimer hunoyl fibrosis
  • ESRD end stage renal disease
  • ADHF Hemodialysis-induced cardiac injury: determinants and outcomes, Clin. J. Am. Soc. Nephrol. 2009; 4:914-920.
  • Nesiritide B-type natriuretic peptide
  • Nesiritide is the recombinant form of the 32 amino acid human B-type natriuretic peptide, which is normally produced by the ventricular myocardium.
  • the drug facilitates cardiovascular fluid homeostasis through counter-regulation of the renin-angiotensin-aldosterone system and promotion of vasodilation, natriuresis, and diuresis.
  • Nesiritide is administered intravenously usually by bolus injection, followed by IV infusion.
  • Atrial natriuretic type peptide is human recombinant atrial natriuretic peptide (ANP), Carperitide, which has been approved for the clinical management of ADHF in Japan since 1995, is also administered via intravenous infusion.
  • ANP human recombinant atrial natriuretic peptide
  • UOP human recombinant urodilatin
  • Ularitide Ularitide
  • Nesiritide In the case of Nesiritide, one recent large study suggested that Nesiritide is ineffective in treating severe heart failure (Lingegowda et al., Long-term outcome of patients treated with prophylactic Nesiritide for the prevention of acute kidney injury following cardiovascular surgery, Clin. Cardiol. 2010; 33(4):217-221). The study concluded that the reno-protection provided by Nesiritide in the immediate postoperative period was not associated with improved long-term survival in patients undergoing high-risk cardiovascular surgery.
  • peptides generally have poor delivery properties due to the presence of endogenous proteolytic enzymes, which are able to quickly metabolize many peptides at most routes of administration.
  • peptides and proteins are generally hydrophilic do not readily penetrate lipophilic biomembranes, and have short biological half-lives due to rapid metabolism and clearance.
  • IM administration could result in slow absorption and possible degradation of the peptide at the injection site.
  • Subcutaneous (SQ) injection can provide a slower absorption rate compared to IM administration and might be useful for long term therapy.
  • potency could be decreased via SQ administration due to degradation and poor absorption.
  • the disclosure provided herein is directed to a study of continuous subcutaneous (SQ) administration of Atrial Natriuretic Peptide (ANP) hormones such as vessel dilator (VD) kaliuretic peptide (KP), and brain natriuretic peptide, generally referred to herein as “natriuretic peptides,” to patients having Kidney Disease (KD) alone, Heart Failure (HF) alone, or KD with concomitant HF.
  • ADP Atrial Natriuretic Peptide
  • VD vessel dilator
  • KP brain natriuretic peptide
  • natriuretic peptides brain natriuretic peptide
  • the continuous subcutaneous administration of a natriuretic peptide can be used to maintain in vivo concentrations of the natriuretic peptide above a critical efficacy threshold for an extended period of time.
  • natriuretic peptides Both bolus and continuous SQ delivery of natriuretic peptides are contemplated.
  • the invention disclosed herein has a number of embodiments that relate to therapeutic regimens and systems for treatment of KD alone, HF alone or KD with concomitant HF.
  • a medical system or method is used to treat a subject having cardiorenal syndrome (CRS).
  • CRS cardiorenal syndrome
  • a medical system or method is used to treat a subject having heart disease.
  • a medical system or method is used to treat a subject having kidney disease.
  • a medical system or method is used to treat a subject having cardiorenal syndrome (CRS) selected from CRS Type I, CRS Type II, CRS Type III, CRS Type IV or CRS Type V.
  • CRS cardiorenal syndrome
  • a medical system or method is used to treat a subject having heart disease selected from chronic heart failure, congestive heart failure, acute heart failure; decompensated heart failure, systolic heart failure, or diastolic heart failure.
  • a medical system or method is used to treat a subject having kidney disease selected from Stage 1 kidney disease, Stage 2 kidney disease, Stage 3 kidney disease, Stage 4 kidney disease, Stage 5 kidney disease, and end-stage renal disease.
  • the systems and methods of the invention are directed to the administration of a natriuretic peptide to a subject for the treatment of KD alone, HF alone, or KD with concomitant HF.
  • the systems and methods of the invention are also useful for treating other renal or cardiovascular diseases, such as congestive heart failure (CHF), dyspnea, elevated pulmonary capillary wedge pressure, chronic renal insufficiency, acute renal failure, cardiorenal syndrome, and diabetes mellitus.
  • CHF congestive heart failure
  • dyspnea dyspnea
  • elevated pulmonary capillary wedge pressure chronic renal insufficiency
  • acute renal failure acute renal failure
  • cardiorenal syndrome and diabetes mellitus
  • the medical system of the invention can contain a drug provisioning component to administer a therapeutically effective amount of natriuretic peptide to a subject suffering from KD alone, HF alone, or KD with concomitant HF, wherein the drug provisioning component maintains a plasma concentration of the natriuretic peptide within a specified range.
  • the medical system can administer the natriuretic peptide subcutaneously, intramuscularly, or intravenously.
  • the medical system delivers an ANP hormone selected from any one of long-acting natriuretic peptide (LANP), kaliuretic peptide (KP), urodilatin (URO), atrial natriuretic peptide (ANP) and vessel dilator (VD) and also brain natriuretic peptide (BNP). Further, the medical system can maintain a plasma concentration of the natriuretic peptide reached during either a subcutaneous bolus of the natriuretic peptides at 6000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptides at 100 ng/kg ⁇ min in the subject.
  • ANP hormone selected from any one of long-acting natriuretic peptide (LANP), kaliuretic peptide (KP), urodilatin (URO), atrial natriuretic peptide (ANP) and vessel dilator (VD) and also brain
  • the medical system can also maintain a plasma concentration of the natriuretic peptide reached during either a subcutaneous bolus of the natriuretic peptides at 18,000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptides at 300 ng/kg ⁇ min in the subject.
  • a therapeutically effective amount of the natriuretic peptide is based at least in part on a volume of distribution for the natriuretic peptide exhibited by the subject.
  • 5 ⁇ x ⁇ 65 ⁇ and i ⁇ y ⁇
  • the volume of distribution for the natriuretic peptide is from any one of about 5 to about 65 L, about 10 to about 25 L, about 5 to about 15 L, about 30 to about 65 L and about 45 to about 65 L.
  • a method for administering a natriuretic peptide such as VD and KP to a subject having KD alone, HF alone, or KD with concomitant HF comprises administering a natriuretic peptide to a subject using a drug provisioning apparatus to maintain a plasma level of the natriuretic peptide in the subject within a specified mean steady state concentration range.
  • This specified concentration is not greater than a plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 6000 ng of the natriuretic peptide per kilogram of the subject's body weight or a plasma level reached by a one hour intravenous infusion of the natriuretic peptide at 100 ng of the natriuretic peptide per kilogram ⁇ minute of the subject's body weight.
  • the specified concentration can also not be greater than a plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 18,000 ng of the natriuretic peptide per kilogram of the subject's body weight or a plasma level reached by a one hour intravenous infusion of the natriuretic peptide at 300 ng of the natriuretic peptide per kilogram ⁇ minute of the subject's body weight.
  • the method can administer the natriuretic peptide subcutaneously, intramuscularly, or intravenously.
  • One route is subcutaneous administration.
  • the method delivers the ANP hormones selected from any one of long-acting natriuretic peptide (LANP), kaliuretic peptide (KP), urodilatin (URO), atrial natriuretic peptide (ANP) and vessel dilator (VD), and also brain natriuretic peptide (BNP).
  • LTP long-acting natriuretic peptide
  • KP kaliuretic peptide
  • UOD urodilatin
  • ANP atrial natriuretic peptide
  • VD vessel dilator
  • BNP brain natriuretic peptide
  • a therapeutic method for treatment of KD alone, HF alone, or KD with concomitant HF is provided is provided.
  • the therapy is based on a method of treatment that effects increased levels of natriuretic peptide.
  • the method includes increasing plasma levels of a natriuretic peptide in a subject having KD alone, HF alone, or KD with concomitant HF is provided by causing the selective release of the natriuretic peptide using a drug provisioning component.
  • the method further includes a control unit consisting of a processor being operably connected to and in communication with the drug provisioning component, wherein the control unit contains a set of instructions that causes the drug provisioning component to administer the natriuretic peptide to the subject according to a therapeutic regimen.
  • the therapeutic regimen is tailored so that the plasma concentration of the natriuretic peptide is maintained within a specified range by effecting controlled administration of the natriuretic peptide using the drug provisioning component.
  • This specified concentration is not greater than a plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 6000 ng of the natriuretic peptide per kilogram of the subject's body weight or a level reached by a one hour intravenous infusion of the natriuretic peptide at 100 ng of the natriuretic peptide per kilogram ⁇ minute of the subject's body weight.
  • This specified concentration can also not be greater than a plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 18,000 ng of the natriuretic peptide per kilogram of the subject's body weight or a level reached by a one hour intravenous infusion of the natriuretic peptide at 300 ng of the natriuretic peptide per kilogram ⁇ minute of the subject's body weight.
  • a second therapeutic method of treating a subject having KD alone, HF alone, or KD with concomitant HF includes increasing plasma or serum concentration of the natriuretic peptide in the subject using the systems of the invention.
  • the method further includes maintaining circulating levels of natriuretic peptide in the plasma or serum of the subject within a specified mean steady state concentration range.
  • the specified mean steady state concentration is not greater than a plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 6000 ng of the natriuretic peptide per kilogram of the subject's body weight or a plasma level reached by a one hour intravenous infusion of the natriuretic peptide at 100 ng of the natriuretic peptide per kilogram ⁇ minute of the subject's body weight.
  • the specified mean steady state concentration is not greater than a plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 18,000 ng of the natriuretic peptide per kilogram of the subject's body weight or a plasma level reached by a one hour intravenous infusion of the natriuretic peptide at 300 ng of the natriuretic peptide per kilogram ⁇ minute of the subject's body weight.
  • the method may further include monitoring one or more physiologic parameters of the subject.
  • the method further includes creating a subject-specific dose-response database using data collected from the subject, evaluating the data in the database, calculating instructions for use with a drug delivery device to maintain a plasma level of the natriuretic peptide in the subject within a specified mean steady state concentration range, and further monitoring subject data and updating the database as necessary.
  • Data collected from the subject could include subject weight, enzyme levels, biomarkers, observed drug clearance, etc.
  • a medical system for administering the natriuretic peptide to a subject having KD alone, HF alone, or KD with concomitant HF is provided.
  • the medical system includes a drug provisioning component that selectively releases a pharmaceutically effective amount of natriuretic peptide to the subject and a control unit consisting of a processor operably connected to and in communication with the drug provisioning component.
  • the control unit is programmed with a set of instructions that causes the drug provisioning component to administer the natriuretic peptide to the subject according to a therapeutic regimen comprising administering a natriuretic peptide to the subject subcutaneously, wherein the therapeutic regimen is sufficient to maintain circulating levels of the natriuretic peptide in the plasma or serum of the subject above a desired mean steady state concentration.
  • the therapeutic regime is selected to maintain serum natriuretic peptide concentrations in the subject at a value not greater than a critical concentration threshold.
  • the critical concentration can be either the plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 6000 ng of the natriuretic peptide per kilogram of the subject's body weight or the plasma level reached by a one hour intravenous infusion of the natriuretic peptide at 100 ng of the natriuretic peptide per kilogram ⁇ minute of the subject's body weight.
  • the critical concentration can also be either the plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 18,000 ng of the natriuretic peptide per kilogram of the subject's body weight or the plasma level reached by a one hour intravenous infusion of the natriuretic peptide at 300 ng of the natriuretic peptide per kilogram ⁇ minute of the subject's body weight.
  • the natriuretic peptides may include any of the atrial natriuretic peptide (ANP) hormones and brain natriuretic peptide (BNP).
  • ANP hormones include long acting natriuretic peptide (LANP), kaliuretic peptide (KP), atrial natriuretic peptide (ANP), vessel dilator (VD), and urodilatin (URO).
  • the drug provisioning component of the medical system may administer the natriuretic peptide to the subject subcutaneously, intramuscularly, or intravenously.
  • a preferred route is subcutaneous administration.
  • a drug provisioning component may consist of any of the following elements: an external or implantable drug delivery pump, an implanted or percutaneous vascular access port, a direct delivery catheter system, and a local drug-release device.
  • the drug provisioning component can deliver the natriuretic peptide at a fixed, pulsed, or variable rate.
  • the drug provisioning component may also be programmable or controllable by a patient who is a subject of the invention.
  • sensors of the medical system of the invention may monitor one or more physiological parameters of the subject obtained by a sensor. These parameters are preferably related to blood pressure or the renal system and can include blood pressure, pulmonary artery pressure, left atrial pressure, right atrial pressure, central venous pressure, lung fluid volume, proteinuria, plasma renin, cardiac output, and glomerular filtration rate.
  • a control unit may operate to regulate the selective release of the natriuretic peptide to maintain a mean steady state concentration using data obtained from the subject.
  • the control unit may further contain computer memory, and the control unit, using the computer memory and processor, may further compile and store a database containing data collected from the subject and also compute a dosing schedule that makes up a part of the therapeutic regimen.
  • a medical system for administering a natriuretic peptide.
  • the medical system has a drug provisioning component to administer a therapeutically effective amount of a natriuretic peptide to a subject suffering from kidney disease alone, heart failure alone, or kidney disease with concomitant heart failure, said drug provisioning component maintaining an effective plasma concentration of the natriuretic peptide based, at least in part, on a volume of distribution for the natriuretic peptide exhibited by the subject.
  • a method for administering a natriuretic peptide is provided.
  • a natriuretic peptide is administered to a subject suffering from kidney disease alone, heart failure, or with concomitant kidney disease and heart failure using a drug provisioning component to maintain a plasma level of the natriuretic peptide at a steady state concentration from about 0.5 to about 60 ng/mL or about 0.5 to about 40 ng/mL, wherein the natriuretic peptide is administered through a subcutaneous route.
  • 0 ⁇ x ⁇ 40 ⁇ and i ⁇ y ⁇
  • 0 ⁇ x ⁇ 60 ⁇ and i ⁇ y ⁇
  • a method for administering a natriuretic peptide is provided.
  • the natriuretic peptide is administered to a subject using a drug provisioning component to maintain a plasma level of the natriuretic peptide at a steady state concentration from about 0.5 to about 40 ng/mL or from about 0.5 to about 60 ng/mL, wherein the natriuretic peptide is administered through a subcutaneous route.
  • a method for administering a natriuretic peptide is provided.
  • the natriuretic peptide is administered to a subject suffering from kidney disease alone, heart failure alone, or with concomitant kidney disease and heart failure using a drug provisioning component based at least in part on a volume of distribution for the natriuretic peptide exhibited by the subject.
  • a specified range of plasma concentration of the natriuretic peptide is not greater than a plasma concentration of the natriuretic peptide reached during either a subcutaneous bolus of the natriuretic peptide at 6000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptide at 100 ng/kg ⁇ min in the subject.
  • a specified range of plasma concentration of the natriuretic peptide range is not greater than a plasma concentration of the natriuretic peptide reached during either a subcutaneous bolus of the natriuretic peptide at 18,000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptide at 300 ng/kg ⁇ min in the subject.
  • a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide in a cyclic on/off pattern at a rate (ng/kg of body weight) for multiple days, wherein the rate results in a plasma concentration of natriuretic peptide not greater than a plasma concentration of the natriuretic peptide reached in the subject during either a subcutaneous bolus at 6000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptide at 100 ng/kg ⁇ min.
  • a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide in a cyclic on/off pattern at a rate (ng/kg of body weight) for multiple days, wherein the rate results in a plasma concentration of natriuretic peptide not greater than a plasma concentration of the natriuretic peptide reached in the subject during either a subcutaneous bolus at 18,000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptide at 300 ng/kg ⁇ min.
  • a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide at a rate (ng/kg of body weight) for 4 hours on and 8 hours off, then 4 hours on and 8 hours off for each of 3 days, wherein the rate results in a plasma concentration of natriuretic peptide not greater than a plasma concentration of the natriuretic peptide reached in the subject during either a subcutaneous bolus at 6000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptide at 100 ng/kg ⁇ min.
  • a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide at a rate (ng/kg of body weight) for 4 hours on and 8 hours off, then 4 hours on and 8 hours off for each of 3 days, wherein the rate results in a plasma concentration of natriuretic peptide not greater than a plasma concentration of the natriuretic peptide reached in the subject during either a subcutaneous bolus at 18,000 ng/kg or a 1 hour.
  • a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide to maintain a plasma level of the natriuretic peptide at a steady state concentration from any one of about 0.5 to about 60 ng/mL, about 0.5 to about 40 ng/mL, about 10 to about 60 ng/mL, about 20 to about 40 ng/mL, about 30 to about 60 ng/mL, about 15 to about 55 ng/mL, about 25 to about 55 ng/mL about 35 to about 55 ng/mL about 23 to about 42 ng/mL about 19 to about 43 ng/mL about 10 to about 50 ng/mL 10 to about 20 ng/mL, about 20 to about 30 ng/mL, about 20 to about 35 ng/mL, about 25 to about 40 ng/mL, and about 30 to about 40 ng/mL.
  • 0 ⁇ x ⁇ 60 ⁇ and i ⁇ y ⁇ R 0 ⁇ y ⁇ (60 ⁇ n) ⁇ .
  • 0 ⁇ x ⁇ 40 ⁇ and i ⁇ y ⁇ R
  • a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide at a continuous rate (ng/kg of body weight) matching the area under the curve of a subcutaneous bolus at 18,000 ng/kg of the subject.
  • a medical system contains a control unit in communication with the drug provisioning component.
  • a drug provisioning component is selected from an external or implantable drug delivery pump, an implanted or percutaneous vascular access port, a direct delivery catheter system, and a local drug-release device.
  • a drug provisioning component is programmable.
  • a drug provisioning component is controlled by a patient who is the subject.
  • a medical system has a control unit having a processor and memory wherein the processor compiles and stores a database of data collected from the subject using a sensor and computes a dosing schedule.
  • data collected from the subject is transmitted via radio frequency by a transmitter, and the data is received by an external controller.
  • data collected from the subject is transmitted and digital instructions returned to the control unit via the Internet.
  • a drug provisioning component and a control unit are co-located.
  • a drug provisioning component, or the control unit are connected or controlled wirelessly.
  • a drug provisioning component is programmed to release a single bolus of 6000 ng of natriuretic peptide per kilogram of the subject's body weight wherein the single bolus is administered three times at 0 hours, 24 hours and 48 hours.
  • a drug provisioning component is programmed to continuously deliver 18,000 ng of natriuretic peptide per kilogram of the subject's body weight over 72 hours.
  • a medical system has a patch pump in communication with a control unit.
  • a specified range of a plasma concentration of the natriuretic peptide is not greater than a plasma concentration of the natriuretic peptide reached during either a subcutaneous bolus of the natriuretic peptide at 18,000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptide at 300 ng/kg ⁇ min in the subject.
  • a drug provisioning component subcutaneously delivers a therapeutically effective amount of the natriuretic peptide at a rate (ng/kg of body weight) for 4 hours on and 8 hours off, then 4 hours on and 8 hours off for each of 3 days, wherein the rate results in a plasma concentration of natriuretic peptide not greater than a plasma concentration of the natriuretic peptide reached in the subject during either a subcutaneous bolus at 6000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptide at 100 ng/kg ⁇ min.
  • a method for administering a natriuretic peptide has the step of compiling and storing data collected from the subject using a processor and memory, and computing a dosing schedule.
  • a method for administering a natriuretic peptide has the step of adjusting a dosing schedule to meet pharmacokinetic variables calculated from one or more subject parameters, wherein the subject parameters include any one of blood pressure, pulmonary artery pressure, left atrial pressure, right arterial pressure, central venous pressure, lung fluid volume, proteinuria, plasma renin, cardiac output, and glomerular filtration rate.
  • a method for administering a natriuretic peptide has the step of collecting data from the subject and transmitting the data via radio frequency to an external controller.
  • a method for administering a natriuretic peptide has the step of collecting and transmitting data from the subject and returning digital instructions to a control unit via the Internet.
  • a method for administering a natriuretic peptide uses a drug provisioning component, and a control unit that are connected or controlled wirelessly.
  • a method for administering a natriuretic peptide uses a drug provisioning component programmed to release a single bolus of 6000 ng of natriuretic peptide per kilogram of the subject's body weight.
  • a method for administering a natriuretic peptide uses a drug provisioning component programmed to release a single bolus of 18,000 ng of natriuretic peptide per kilogram of the subject's body weight.
  • a method for administering a natriuretic peptide uses a single bolus repeated three times.
  • a method for administering a natriuretic peptide uses a drug provisioning component programmed to continuously deliver 6,000 ng of natriuretic peptide per kilogram of the subject's body weight.
  • a method for administering a natriuretic peptide uses a drug provisioning component programmed to continuously deliver 18,000 ng of natriuretic peptide per kilogram of the subject's body weight.
  • a method for administering a natriuretic peptide has the step of using a patch pump in communication with a control unit.
  • a method for administering a natriuretic peptide maintains a plasma concentration of the natriuretic peptide at a steady state concentration at a specified range from about 0.5 to about 40 ng/mL.
  • 0 ⁇ x ⁇ 60 ⁇ and i ⁇ y ⁇
  • 0 ⁇ x ⁇ 40 ⁇ and i ⁇ y ⁇
  • a method for administering a natriuretic peptide maintains a plasma concentration of the natriuretic peptide at a steady state concentration at a specified range at any one of about 10 to 60 ng/mL, about 10 to about 20 ng/mL, about 20 to about 30 ng/mL, about 20 to about 35 ng/mL, about 25 to about 40 ng/mL, and about 30 to about 40 ng/mL.
  • a method for administering a natriuretic peptide is performed on a subject exhibiting a subcutaneous adsorption half-life for the natriuretic peptide from any one of about 0 to about 60 minutes, 0 to about 5 minutes, 15 to about 25 minutes, 0 to about 30 minutes, and 15 to about 30 minutes.
  • a method for administering a natriuretic peptide is performed on a subject exhibiting a subcutaneous adsorption half-life for the natriuretic peptide of about 20 minutes.
  • a method for administering a natriuretic peptide is performed, wherein the natriuretic peptide is administered to a subject at a rate from any one of about 10 to about 300 ng/kg ⁇ min, about 10 to about 150 ng/kg ⁇ min, about 25 to about 145 ng/kg ⁇ min, about 30 to about 140 ng/kg ⁇ min, about 35 to about 125 ng/kg ⁇ min, about 50 to about 120 ng/kg ⁇ min, about 65 to about 115 ng/kg ⁇ min, and about 85 to about 110 ng/kg ⁇ min of the subject's body weight.
  • a method for administering a natriuretic peptide is performed wherein from about 0.6 to about 9 ⁇ g of the natriuretic peptide is administered to the subject per kg of the subject's body weight in an hour time period.
  • a method for administering a natriuretic peptide is performed wherein the natriuretic peptide is administered to a subject at a rate from any one of about 1 to about 8 ⁇ g, about 2 to about 5 ⁇ g, about 3 to about 4 ⁇ g, about 1 to about 7 ⁇ g, about 3 to about 5 ⁇ g, about 2 to about 6 ⁇ g, about 7 to about 9 ⁇ g, and about 8 to about 9 ⁇ g of the natriuretic peptide is administered to the subject per kg of the subject's body weight in an hour time period.
  • a method for administering a natriuretic peptide is performed wherein the natriuretic peptide is vessel dilator (VD).
  • VD vessel dilator
  • a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide at a continuous rate (ng/kg of body weight) matching the area under the curve of a subcutaneous bolus at 6000 ng/kg of the subject.
  • a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide to maintain a plasma level of the natriuretic peptide at a steady state concentration from any one of about 0.5 to about 60 ng/mL, about 0.5 to about 40 ng/mL, about 10 to about 60 ng/mL, about 20 to about 40 ng/mL, about 30 to about 60 ng/mL, about 15 to about 55 ng/mL, about 25 to about 55 ng/mL about 35 to about 55 ng/mL about 23 to about 42 ng/mL about 19 to about 43 ng/mL about 10 to about 50 ng/mL 10 to about 20 ng/mL, about 20 to about 30 ng/mL, about 20 to about 35 ng/mL, about 25 to about 40 ng/mL, and about 30 to about 40 ng/mL.
  • the drug provisioning component can deliver the natriuretic peptide at a fixed, pulsed, or variable rate.
  • a drug provisioning component can consist of any of the following elements: an external or implantable drug delivery pump, an implanted or percutaneous vascular access port, a direct delivery catheter system, and a local drug-release device.
  • a drug provisioning component can subcutaneously deliver a therapeutically effective amount of the natriuretic peptide at a continuous rate (ng/kg of body weight) matching the area under the curve of a subcutaneous bolus at 6000 ng/kg of the subject.
  • any specified range is in addition to an endogenous concentration of the natriuretic peptide.
  • the natriuretic peptide is selected from any one of long-acting natriuretic peptide (LANP), kaliuretic peptide (KP), urodilatin (URO), atrial natriuretic peptide (ANP), vessel dilator (VD), and brain natriuretic peptide (BNP).
  • LTP long-acting natriuretic peptide
  • KP kaliuretic peptide
  • UEO urodilatin
  • ABP atrial natriuretic peptide
  • VD vessel dilator
  • BNP brain natriuretic peptide
  • a method for administering a natriuretic peptide uses a drug provisioning component selected from an external or implantable drug delivery pump, an implanted or percutaneous vascular access port, a direct delivery catheter system, and a local drug-release device.
  • FIG. 1 shows the pharmacokinetic model of the subcutaneous injection as compared to an estimated model of the equivalent intravenous (IV) dosage for Vessel Dilator (VD) peptide.
  • FIG. 2 shows a disposable external infusion pump.
  • FIG. 3 shows the pharmacokinetic model for IV infusion at two different dosages.
  • FIG. 4 shows the pharmacokinetic model for IV infusion with varying half-life for elimination.
  • FIG. 5 shows the pharmacokinetic model for single bolus subcutaneous injections with instantaneous absorption and varying half-life for elimination.
  • FIG. 6 shows the pharmacokinetic model for IV infusion as compared to an estimated model of the equivalent dosage by single subcutaneous bolus.
  • FIG. 7 shows the pharmacokinetic model for single bolus subcutaneous injections with varying half-life for elimination combined with a half-life for absorption of the administered peptide.
  • FIG. 8 shows the pharmacokinetic model for single bolus subcutaneous injections with varying half-life for absorption.
  • FIG. 9 shows the pharmacokinetic model for IV infusion as compared to an estimated model of the equivalent dosage by single subcutaneous bolus with varying half-life for absorption.
  • FIG. 10 shows a detailed view of the pharmacokinetic model from FIG. 9 .
  • FIGS. 11A and 11B show the measured plasma concentration of VD in canines at a total dose of 7.2 mg/kg and 14.4 mg/kg, respectively.
  • FIGS. 12A and 12B show dose normalized AUC ⁇ and dose normalized C max for observed plasma concentration of VD in canines.
  • FIGS. 13A and 13B show the dose dependence of AUC ⁇ and C avg for observed plasma concentration of VD observed in rats.
  • FIG. 14 shows the time-dependent observation of plasma concentration for VD in male rats receiving continuous subcutaneous administration of VD.
  • the open triangle represents a suspected outlier measurement excluded from the trend line.
  • FIG. 15 shows the time-dependent observation of plasma concentration for VD in female rats receiving continuous subcutaneous administration of VD.
  • FIG. 16 shows glomerular filtration rates for a canine heart failure model treated with a natriuretic peptide.
  • FIG. 17 shows a change in urine flow rate for a canine heart failure model treated with a natriuretic peptide.
  • FIG. 18 shows a change in sodium excretion rate for a canine heart failure model treated with a natriuretic peptide.
  • FIG. 19 shows right atrial pressures for a canine heart failure model treated with a natriuretic peptide.
  • FIG. 20 shows pulmonary capillary wedge pressures for a canine heart failure model treated with a natriuretic peptide.
  • FIG. 21 shows Pre-proANF (56-92) plasma concentration data for a canine heart failure model treated with natriuretic peptide.
  • FIGS. 22 A and B show a change in blood pressure for a rat model treated with a natriuretic peptide.
  • FIG. 23 shows a change in albumin excretion for a rat model treated with a natriuretic peptide.
  • FIGS. 24 A and B show a change in protein excretion for a rat model treated with a natriuretic peptide.
  • FIG. 25 shows a change in renal cortical blood flow for a rat model treated with a natriuretic peptide.
  • FIG. 26 shows a change in creatinine clearance for a rat model treated with a natriuretic peptide
  • FIG. 27 shows serum urea levels for a rat model treated with a natriuretic peptide.
  • FIG. 28 shows urine cGMP levels for a rat model treated with a natriuretic peptide.
  • FIG. 29 shows serum prostaglandin E 2 levels for a rat model treated with a natriuretic peptide.
  • FIG. 30 shows an assessment schedule for screening prior to infusion and during a 6-hour subcutaneous infusion session.
  • FIG. 31 shows an assessment for after a 6-hour subcutaneous infusion session.
  • the invention relates to selective delivery of a natriuretic peptide using a drug provisioning component that can include infusion pumps, implanted or percutaneous vascular access ports, direct delivery catheter systems, local drug-release devices or any other type of medical device that can be adapted to deliver a therapeutic to a subject.
  • the drug provisioning component can administer the natriuretic peptide subcutaneously, intramuscularly, or intravenously at a fixed, pulsed, continuous or variable rate.
  • a preferred embodiment of the invention contemplates subcutaneous delivery using an infusion pump at a continuous rate to maintain a specified plasma concentration of the natriuretic peptides.
  • Natriuretic peptides and their sequences are disclosed in U.S. Pat. No. 5,691,310 and U.S. Patent App. Pub. Nos. 2006/0205642, 2008/0039394, 2009/0062206, and 2009/0170196, each of which is incorporated by reference herein in its entirety.
  • an element means one element or more than one element.
  • administering can be used interchangeably to indicate the introduction a compound, agent or peptide into the body of a patient, including methods of introduction where the compound, agent or peptide will be present in the blood or plasma of a subject to whom the compound, agent or peptide is administered.
  • phrases “consisting essentially of” includes any elements listed after the phrase and is limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase indicates that the listed elements are required or mandatory but that other elements are optional and may or may not be present, depending upon whether or not they affect the activity or action of the listed elements.
  • “Pharmaceutically acceptable” is meant to encompass any carrier, which does not interfere with effectiveness of the biological activity of the active ingredient and that is not toxic to the host to which it is administered.
  • Drug provisioning component encompasses any and all devices that administers a therapeutic agent to a subject and includes infusion pumps, implanted or percutaneous vascular access ports, direct delivery catheter systems, local drug-release devices or any other type of medical device that can be adapted to deliver a therapeutic to a subject.
  • the drug provisioning component and the control unit may be “co-located,” which means that these two components, in combination, may make up one larger, unified unit of a system.
  • programmable refers to a device using computer hardware architecture and being capable of carrying out a set of commands, automatically.
  • Glomerular filtration rate describes the flow rate of filtered fluid through the kidney.
  • the estimated glomerular filtration rate or “eGFR” is a measure of filtered fluid based on a creatinine test and calculating the eGFR based on the results of the creatinine test.
  • Intravenous delivery refers to delivery of an agent by means of a vein.
  • “Intramuscular” delivery refers to delivery of an agent by means of muscle tissue.
  • Subcutaneous delivery refers to delivery of an agent by means of the subcutis layer of skin directly below the dermis and epidermis.
  • a “patch pump” is a device that adheres to the skin, contains a medication, and can deliver the drug over a period of time, either transdermally or via an integrated subcutaneous mini-catheter.
  • delivering can be used interchangeably to indicate the introduction of a therapeutic or diagnostic agent into the body of a subject in need thereof to treat a disease or condition, and can further mean the introduction of any agent into the body for any purpose.
  • the “field of chronic delivery” involves the following four parameters: period of treatment, scope, route of administration, and method of delivery.
  • “Chronic delivery” means a period of treatment or drug delivery of more than 24 hours, even if the drug is not delivered continuously for that period of time.
  • the scope of delivery involves one or more drugs, in any combination.
  • the route of administration includes, but is not limited to, subcutaneous, intravascular, intraperitoneal and direct to organ, as described in further detail herein.
  • the method of delivery includes, but is not limited to, implanted and external pumps, programmed or fixed rate, implanted or percutaneous vascular access ports, depot injection, direct delivery catheter systems, and local controlled release technology, as described in further detail herein.
  • the “field of acute delivery” involves the same four parameters as for the field of chronic delivery. The difference between the two fields is the period of treatment.
  • “Acute delivery” means a period of treatment or drug delivery of less than or equal to 24 hours, even if the drug is delivered continuously for that period of time.
  • terapéuticaally effective amount refers to an amount of an agent (e.g., atrial natriuretic peptides) effective to treat at least one symptom of a disease or disorder in a subject.
  • the “therapeutically effective amount” of the agent for administration may vary based upon the desired activity, the diseased state of the subject being treated, the dosage form, method of administration, subject factors such as the subject's sex, genotype, weight and age, the underlying causes of the condition or disease to be treated, the route of administration and bioavailability, the persistence of the administered agent in the body, evidence of natriuresis and/or diuresis, the type of formulation, and the potency of the agent.
  • treating refers to the management and care of a patient having a pathology or condition for which administration of one or more therapeutic compounds or peptides is indicated for the purpose of combating or alleviating symptoms and complications of the condition. Treating includes administering one or more formulations or peptides of the present invention to prevent or alleviate the symptoms or complications or to eliminate the disease, condition, or disorder.
  • treatment or “therapy” refers to both therapeutic treatment and prophylactic or preventative measures.
  • Treating does not require complete alleviation of signs or symptoms, does not require a cure, and includes protocols having only a marginal or incomplete effect on a patient.
  • therapeutic regimen refers to, for example, a part of a treatment plan for an individual suffering from a pathological condition that specifies factors such as the agent or agents to be administered to the patient or subject, the doses of such agent(s), the schedule and duration of the treatment, etc.
  • an “infusion device” or “infusion pump” describes a means for delivering an infusion liquid into a patient or subject subcutaneously, intravenously, arterially, or by any other route of administration.
  • the infusion pump has three major components: a fluid reservoir, a catheter system for transferring the fluids into the body, and a device that generates and/or regulates flow of the infusion fluid to achieve a desired concentration of a therapeutic agent in the body.
  • a fluid reservoir for transferring the fluids into the body
  • a catheter system for transferring the fluids into the body
  • a device that generates and/or regulates flow of the infusion fluid to achieve a desired concentration of a therapeutic agent in the body.
  • the infusion fluid of the invention can be delivered and regulated using either roller pumps or electro-kinetic pumping (also known as electro-osmotic flow).
  • Examples of infusion devices further include, but are not limited to, an external or an implantable drug delivery pumps.
  • continuous infusion system refers to a collection of components for continuously administering a fluid to a patient or subject for an extended period of time without having to establish a new site of administration each time the fluid is administered.
  • the fluid in the continuous infusion system typically contains a therapeutic agent or agents.
  • the system typically has one or more reservoir(s) for storing the fluid(s) before it is infused, a pump, a catheter, cannula, or other tubing for connecting the reservoir to the administration site via the pump, and control elements to regulate the pump.
  • the device may be constructed for implantation, usually subcutaneously. In such a case, the reservoir will usually be adapted for percutaneous refilling.
  • continuous administration and “continuous infusion” are used interchangeably herein and mean delivery of an agent, such as an atrial natriuretic peptide, in a manner that, for example, avoids fluctuations in the in vivo concentrations of the agent throughout the course of a treatment period.
  • Delivery as used herein, can mean any type of means to effect a result either by electrical, mechanical or other physical means.
  • a “deliverable amount” is defined as any amount of a measured fluid that can be delivered through a fluid delivery catheter as known by those of ordinary skill in the art. “Delivery” as used herein generally, can mean any type of means to effect a result either by electrical, mechanical or other physical means.
  • “Risk” relates to the possibility or probability of a particular event occurring either presently or at some point in the future.
  • subject and “patient” can be used interchangeably, and describe a member of any animal species, preferably a mammalian species, optionally a human.
  • the animal species can be a mammal or vertebrate such as a primate, rodent, lagomorph, domestic animal or game animal.
  • Primates include chimpanzees, cynomologous monkeys, spider monkeys, and macaques, e.g., Rhesus or Pan.
  • Rodents and lagomorphs include mice, rats, woodchucks, ferrets, rabbits and hamsters.
  • Domestic and game animals include cows, horses, pigs, sheep, deer, bison, buffalo, mink, felines, e.g., domestic cat, canines, e.g., dog, wolf and fox, avian species, e.g., chicken, turkey, emu and ostrich, and fish, e.g., trout, catfish and salmon.
  • the subject can be an apparently healthy individual, an individual suffering from a disease, or an individual being treated for a disease.
  • sample refers to a quantity of a biological substance that is to be tested for the presence or absence of one or more molecules.
  • Renin also known as angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system (RAS), which regulates the body's mean arterial blood pressure by mediating extracellular volume (i.e., that of the blood plasma, lymph and interstitial fluid) and arterial vasoconstriction. Renin is released by the kidney when a subject has decreased sodium levels or low blood volume.
  • RAS renin-angiotensin system
  • Endogenous substances are those that originate from within an organism, tissue, or cell.
  • Pharmacokinetics is used according to its meaning accepted in the art and refers to the study of the action of drugs in the body. Pharmacokinetics includes, for example, the effect and duration of drug action, and the rate at which the drug is absorbed, distributed, metabolized, and eliminated by the body.
  • AUC area under the curve
  • C(t) indicates the concentration of the drug in the plasma at time t.
  • “Half-life” or “half-time” as used herein in the context of administering a peptide drug to a patient is defined as the time required for the blood plasma concentration of a substance to halve (“plasma half-life”) its steady state.
  • plasma half-life the time required for the blood plasma concentration of a substance to halve
  • the knowledge of half-life is useful for the determination of the frequency of administration of a drug for obtaining a desired plasma concentration.
  • the half-life of a particular drug is independent of the dose administered.
  • alpha and beta half-lives are defined such that the alpha phase is associated with redistribution, and the beta phase is associated with clearance.
  • protein drugs that are, for the most part, confined to the bloodstream, there can be at least two clearance half-lives.
  • “Elimination” refers to the removal or transformation of a drug in circulation, usually via the kidney and liver.
  • “Elimination half-life” is the time required for the amount of drug in the body to decrease by 50%.
  • “Absorption” refers to the transition of drug from the site of administration to the blood circulation.
  • measured range contemplates both a measured value, such as the concentration value of an agent or peptide in the plasma of a patient, and a measured value that is either added or subtracted from a normal or basal level of a subject.
  • Loading dose refers to the dose(s) of drugs given at the onset of therapy to rapidly provide a therapeutic effect. Use of a loading dose prior to a maintenance dosage regimen will shorten the time required to approach a steady state.
  • steady state represents the equilibrium between the amount of drug given and the amount eliminated over the dosing interval. In general, it takes drug four to five half-lives to reach a steady state, however the multiple can vary depending on the route of administration. Sampling should occur when the drug has reached its steady state to judge efficacy and toxicity of the drug therapy. Steady state should not be confused with the therapeutic range.
  • Css “Mean steady state concentration,” denoted by “Css” refers to the concentration of a drug or chemical in a body fluid, usually plasma, at the time a “steady state” has been achieved and rates of drug administration and drug elimination are equal. Steady state concentrations fluctuate between a maximum (peak) (“Cmax”) and minimum (trough) (“Cmin”) concentration with each dosing interval. Css is a value approached as a limit and is achieved following the last of an infinite number of equal doses given at equal intervals.
  • Phenosma concentration refers to the amount of a drug in the blood plasma of the patient.
  • Maximum plasma concentration refers to the maximum amount of a drug observed in the blood of a patient or subject.
  • Average plasma concentration (C avg ) refers to the average amount of a drug observed in the blood of a patient or subject over a time course of a period of observation of the amount of the drug in the blood.
  • Minimum plasma concentration refers to the minimum amount of a drug observed in the blood of a patient or subject over a time course of a period of observation of the amount of the drug in the blood.
  • Time to maximum concentration refers to the time observed to reach maximum plasma concentration of a drug as measured from the initiation of regimen of administration of the drug.
  • Percent fluctuation refers to the difference between C max and C min for a drug in the blood over a time course of a period of observation of the amount of the drug in the blood, where
  • VOD volume of distribution
  • “Pharmacokinetic constraints,” as used herein, describes any factor that determines the pharmacokinetic profile of a drug such as immunogenicity, route of administration, endogenous concentrations of the natriuretic peptides, diurnal variation, and rate of drug delivery.
  • a “dose-response” relationship describes how the likelihood and severity of adverse health effects (i.e., the responses) are related to the amount and condition of exposure to an agent (i.e., the dose provided).
  • Dose-response assessment is a two step process. The first step involves an assessment of all data that are available or can be gathered through experiments, in order to document the dose-response relationship(s) over the range of observed doses (i.e., the doses that are reported in the data collected). However, frequently this range of observation may not include sufficient data to identify a dose where the adverse effect is not observed (i.e., the dose that is low enough to prevent the effect) in the human population.
  • the second step consists of extrapolation to estimate the risk, or probably of adverse effect, beyond the lower range of available observed data to make inferences about the critical region where the dose level begins to cause the adverse effect in the test population.
  • a “dose-response database,” as used in the invention is a computer database that stores the data collected for dose-response assessment.
  • the database thus provides inputs for mathematical modeling for computing risk of various adverse effects that are to be associated with the drug and certain doses of the drug.
  • Patient parameters includes parameters that may affect the efficacy of therapy or indicate a parameter that affects the efficacy of therapy, e.g., activity, activity level, posture, or a physiological parameter of the patient or subject.
  • Other physiological patient parameters include heart rate, respiration rate, respiratory volume, core temperature, blood pressure, blood oxygen saturation, partial pressure of oxygen within blood, partial pressure of oxygen within cerebrospinal fluid, muscular activity, arterial blood flow, electromyogram (EMG), an electroencephalogram (EEG), an electrocardiogram (ECG), or galvanic skin response.
  • “Selective release” of an atrial natriuretic peptide as used in the invention describes the controlled delivery of a therapeutic using the drug delivery component, and can also refer to a controlled or programmed release of the atrial natriuretic peptide into the vasculature of the patient, according to a treatment protocol, through use of the drug provisioning component.
  • a “subcutaneous bolus injection” is the subcutaneous administration of a “bolus,” of a medication, drug or other compound that is given to a subject to raise concentration of the compound in the subject's blood to a desired level. Specifically, the injection is made in the subcutis, the layer of skin directly below the dermis and epidermis, collectively referred to as the cutis.
  • the bolus injection may be delivered using a pump that may be programmable.
  • an “intra-arterial fluid delivery catheter,” or the phrase “catheter specially adapted for insertion in an artery” is defined as a small tube configured for insertion into an artery for the purpose of delivering a fluid into the circulatory system of the patient.
  • an “intravenous fluid delivery catheter” is defined as a small tube configured for insertion into a vein for the purpose of delivering a fluid into the circulatory system of the patient.
  • distal tip of a catheter is the end that is situated farthest from a point of attachment or origin, and the end closest to the point of attachment or origin is known as the “proximal” end.
  • Vascular access ports are ports for infusing and/or withdrawing fluid from a patient.
  • the vascular access or infusion ports typically incorporate mechanical valves which open during use, such as when a needle is inserted into the port, and close in between use, such as when a needle is removed from the part.
  • the ports can be positioned subcutaneously underneath the skin, or percutaneously when the access part of the port is placed above the level of the skin to be accessed without skin penetration eliminating the need for using needle sticks to access the vasculature.
  • Vascular access devices may also be implantable. These devices typically consist of a portal body and a catheter. The catheter may be either integral with the portal body or separate from the body to be attached at the time of implantation.
  • a “direct delivery catheter system,” as used herein is a catheter system for guiding an elongated medical device into an internal bodily target site.
  • the system can have a distal locator for locating a target site prior to deployment of the catheter.
  • the catheter can be introduced through a small incision into the bodily vessel, channel, canal, or chamber in question; or into a bodily vessel, channel, canal, or chamber that is otherwise connected to the site of interest (or target site), and then guided through that vessel to the target site.
  • peptide describes an oligopeptide, polypeptide, peptide, protein or glycoprotein, and includes a peptide having a sugar molecule attached thereto.
  • “native form” means the form of the peptide when produced by the cells and/or organisms in which it is found in nature. When the peptide is produced by a plurality of cells and/or organisms, the peptide may have a variety of native forms.
  • “Peptide” can further refer to a polymer in which the monomers are amino acids that are joined together through amide bonds.
  • peptides which have been modified using ordinary molecular biological techniques so as to improve their resistance to proteolytic degradation or to optimize solubility properties or to render them more suitable as a therapeutic agent.
  • Analogs of such peptides include those containing residues other than naturally occurring L-amino acids, e.g., D-amino acids or non-naturally occurring synthetic amino acids.
  • the present invention also embraces recombination peptides such as recombinant human ANP (hANP) obtained from bacterial cells after expression inside the cells.
  • hANP recombinant human ANP
  • peptides and recombinant peptides of the present invention can be made by varied methods of manufacture wherein the peptides of the invention are not limited to the products of any of the specific exemplary processes listed herein.
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, ⁇ -carboxyglutamate, and O-phosphoserine.
  • the present invention also provides for analogs of proteins or peptides which comprise a protein as identified above.
  • fragment refers to a polypeptide that comprises at least six contiguous amino acids of a polypeptide from which the fragment is derived.
  • a fragment refers to a polypeptide that comprises at least 10 contiguous amino acids of a polypeptide from which the fragment is derived, more preferably at least 10 contiguous amino acids, still more preferably at least 15 contiguous amino acids, and still more preferably at least 20 contiguous amino acids of a polypeptide from which the fragment is derived.
  • natriuretic peptide fragment refers to a fragment of any natriuretic peptide defined and described herein.
  • Cardiovascular disease refers to various clinical diseases, disorders or conditions involving the heart, blood vessels, or circulation. Cardiovascular disease includes, but is not limited to, coronary artery disease, peripheral vascular disease, hypertension, myocardial infarction, and heart failure.
  • natriuretic or “natriuresis” refer to the ability of a substance to increase sodium clearance from a subject.
  • renal or cardiovascular protective and “renal or cardiovascular protective effects” refer to the ability of a substance to improve one or more functions of the kidneys or heart of a subject, including natriuresis, diuresis, cardiac output, hemodynamics, renal cortical blood flow or glomerular filtration rate, or to lower the blood pressure of the subject. Any measurable diagnostic factor that would be recognized by one having skill in the art as reducing stress on the kidneys and/or heart or as evidence of improvement in the function of the renal or cardiovascular system can be considered a renal or cardiovascular protective effect.
  • the term “renal protective” or “renal protective effect” refers to a measurable diagnostic factor that would be recognized by one having skill in the art as particularly related to an indication of reduced stress on the kidneys or improvement in renal function.
  • cardiac protective or “cardiovascular protective effect” refers to a measurable diagnostic factor that would be recognized by one having skill in the art as particularly related to an indication of reduced stress on the cardiovascular system or improvement in cardiac function.
  • heart failure refers to a condition in which the heart cannot pump blood efficiently to the rest of the body.
  • Heart failure may be caused by damage to the heart or narrowing of the arteries due to infarction, cardiomyopathy, hypertension, coronary artery disease, valve disease, birth defects or infection.
  • Heart failure may also be further described as chronic, congestive, acute, decompensated, acute decompensated, systolic, or diastolic.
  • the NYHA classification describes the severity of the disease based on functional capacity of the patient and is incorporated herein by reference.
  • Heart failure can be with preserved ejection fraction or be with reduced ejection fraction. Further, heart failure can include left heart failure or right heart failure.
  • Acute heart failure means a sudden onset or episode of an inability of the heart to pump a sufficient amount of blood with adequate perfusion and oxygen delivery to internal organs. Acute heart failure can be accompanied by congestion of the lungs, shortness of breadth and/or edema.
  • “increased severity” of cardiovascular disease refers to the worsening of the disease as indicated by increased New York Heart Association (NYHA) classification
  • “reduced severity” of cardiovascular disease refers to an improvement of the disease as indicated by reduced NYHA classification.
  • the “renal system,” as defined herein, comprises all the organs involved in the formation and release of urine including the kidneys, ureters, bladder and urethra.
  • Proteinuria is a condition in which urine contains an abnormal amount of protein.
  • Albumin is the main protein in the blood; the condition where the urine contains abnormal levels of albumin is referred to as “albuminuria.”
  • Healthy kidneys filter out waste products while retaining necessary proteins such as albumin.
  • Most proteins are too large to pass through the glomeruli into the urine.
  • proteins from the blood can leak into the urine when the glomeruli of the kidney are damaged.
  • KD kidney disease
  • Kidney disease is a condition characterized by the slow loss of kidney function over time. The most common causes of KD are high blood pressure, diabetes, heart disease, and diseases that cause inflammation in the kidneys. Kidney disease can also be caused by infections or urinary blockages. If KD progresses, it can lead to end-stage renal disease (ESRD), where the kidneys fail completely.
  • ESRD end-stage renal disease
  • CRS Type I Acute Cardiorenal Syndrome
  • CRS Type II Chronic Cardiorenal syndrome
  • CRS Type II Acute Renocardiac Syndrome
  • renal function e.g., acute kidney ischaemia or glomerulonephritis
  • CRS Type IV Chronic Renocardiac syndrome
  • kidney disease e.g., chronic glomerular disease
  • CRS Type V Secondary Cardiorenal Syndrome
  • KD can be referred to by different stages indicated by Stages 1 to 5. Stage of KD can be evaluated by glomerular filtration rate of the renal system. Stage 1 KD can be indicated by a GFR greater than 90 mL/min/1.73 m 2 with the presence of pathological abnormalities or markers of kidney damage. Stage 2 KD can be indicated by a GFR from 60-89 mL/min/1.73 m 2 , Stage 3 KD can be indicated by a GFR from 30-59 mL/min/1.73 m 2 and Stage 4 KD can be indicated by a GFR from 15-29 mL/min/1.73 m 2 .
  • KD as defined in the present invention, contemplates KD regardless of the direction of the pathophysiological mechanisms causing KD and includes CRS Type II and Type IV and Stage 1 through Stage 5 KD among others. Kidney disease can further include acute renal failure, acute kidney injury, and worsening of renal function.
  • Hemodynamics is the study of blood flow or circulation. The factors influencing hemodynamics are complex and extensive but include cardiac output (CO), circulating fluid volume, respiration, vascular diameter and resistance, and blood viscosity. Each of these may in turn be influenced by physiological factors. Hemodynamics depends on measuring the blood flow at different points in the circulation. Blood pressure is the most common clinical measure of circulation and provides a peak systolic pressure and a diastolic pressure. “Blood pressure” (BP) is the pressure exerted by circulating blood upon the walls of blood vessels. Invasive hemodynamic monitoring measures pressures within the heart. One of the most widely used methods of hemodynamic monitoring is the use of the Swan-Ganz Catheter. Through the use of the Swan-Ganz catheter one can measure central venous pressure (CVP) and obtain a subject's CO.
  • CVP central venous pressure
  • Central venous pressure describes the pressure of blood in the thoracic vena cava, near the right atrium of the heart. CVP reflects the amount of blood returning to the heart and the ability of the heart to pump the blood into the arterial system.
  • Another method for obtaining the cardiac output is using the Fick Method, in which a port is disposed in the pulmonary artery and measures pulmonary artery pressures. This port can also be configured to have a balloon that when inflated measures the pulmonary artery wedge pressure (PCWP).
  • PCWP pulmonary artery wedge pressure
  • MAP Mean arterial pressure
  • LAP Left atrial pressure
  • Pulmonary artery wedge pressure is used to provide an indirect estimate of LAP.
  • left ventricular pressure can be directly measured by placing a catheter into the left ventricle by feeding it through a peripheral artery, into the aorta, and then into the ventricle, it is not feasible to advance this catheter back into the left atrium.
  • LAP can be measured by placing a special catheter into the right atrium then punching through the interatrial septum; however, this is not usually performed because of damage to the septum and potential harm to the patient.
  • Remote atrial pressure refers to the pressure in the right atrium of the heart. Central venous pressure is used to provide an indirect, noninvasive, measure of right atrial pressure.
  • Intrinsic is used herein to describe something that is situated within or belonging solely to the organ or body part on which it acts. Therefore, “intrinsic natriuretic peptide generation” refers to a subject's making or releasing of one or more natriuretic peptides by its respective organ(s).
  • a “buffer solution” is an aqueous solution consisting of a mixture of a weak acid and its conjugate base or a weak base and its conjugate acid. It has the property that the pH of the solution changes very little when a small amount of strong acid or base is added to it. Buffer solutions are used as a means of keeping pH at a nearly constant value in a wide variety of chemical applications.
  • “Buffered saline solution,” as used herein, refers to a phosphate buffered saline solution, which is a water-based salt solution containing sodium chloride, sodium phosphate, and (in some formulations) potassium chloride and potassium phosphate. The buffer helps to maintain a constant pH. The osmolarity and ion concentrations of the solution usually match those of the human body.
  • a “control system” consists of combinations of components that act together to maintain a system to a desired set of performance specifications.
  • the performance specifications can include sensors and monitoring components, processors, memory and computer components configured to interoperate.
  • a “controller” or “control unit” is a device which monitors and affects the operational conditions of a given system.
  • the operational conditions are typically referred to as output variables of the system, which can be affected by adjusting certain input variables.
  • in communication it is meant that the elements of the system of the invention are so connected, either directly or remotely, wirelessly or by direct electrical contact so that data and instructions can be communicated among and between said elements.
  • Controlled delivery refers to the implementation of a controller or control unit that is either programmable or patient-controlled that causes the drug delivery component to administer the therapeutic agent to the patient according to a programmed administration protocol or in response to a command given by the patient or a healthcare provider.
  • Patient controlled delivery refers to mechanisms by which the patient can administer and/or control the administration of a drug. Thus, the patient can cause the drug delivery component to administer the therapeutic formulation.
  • a cyclic on/off pattern as used herein means a repetitive condition which alternates between being in “on” and “off” states. Such conditions may pertain to drug delivery by a drug provisioning component of a medical system wherein the “on” state denotes a period of drug delivery. A drug administered in “a cyclic on/off pattern” is delivered as repetitive doses over duration of time.
  • maintaining a plasma concentration refers to, in some embodiments, maintaining a concentration of a compound or peptide in the plasma of a subject at a recited or referenced concentration range by administration of the compound or peptide by any appropriate means.
  • “maintaining a plasma concentration” refers to maintaining a concentration of a compound or peptide at a concentration in the plasma of a subject that is in addition to an endogenous concentration of that compound or peptide.
  • a subject can have an endogenous baseline of that compound or peptide measurable in the plasma. Maintaining a plasma concentration at a recited concentration can refer to increasing the plasma concentration of the compound or peptide by the recited amount and maintaining a plasma concentration at that elevated amount.
  • multiple days refers to any duration of time greater than 24 hours.
  • pulmonary capillary wedge pressure refers to the pressure measured by wedging a pulmonary catheter with a deflated balloon into a small pulmonary arterial branch.
  • Measurements of pharmacokinetic variables such as steady state concentration, absorption half-life, administration rate, volume of distribution, elimination half-life, and clearance are described as ranges.
  • the measurement ranges are represented by equations encompassing groups of ranges. Specifically, the values of pharmacokinetic variables are described as ranges from n to (n+i), wherein the definitions of n and i are specific to a particular pharmacokinetic variable. It is to be understood that a given range supports every possible permutation thereof, and accordingly all such permutations are therefore contemplated by the invention.
  • ⁇ x ⁇ , for ⁇ 0, and i ⁇ y ⁇ R
  • 0 ⁇ y ⁇ ( ⁇ n) ⁇ , or n ⁇ x ⁇ R
  • ⁇ x ⁇ for ⁇ 0, and i ⁇ y ⁇ R
  • ⁇ is a minimum value specific to a pharmacokinetic variable
  • ⁇ is a maximum value specific to a pharmacokinetic variable.
  • a range from n to (n+i) where n ⁇ x ⁇ R
  • 0 ⁇ x ⁇ 500 ⁇ , and i ⁇ y ⁇ R
  • 0 ⁇ y ⁇ (500 ⁇ n) ⁇ , would encompass all values ranging from greater than 0 up to and including 500, and additionally all sub-ranges within the range of 0 to 500.
  • the lower bound of the sub-range would be 10
  • the upper bound could be any value from 10 to 500, thus yielding sub-ranges such as 10-10, 10-10.5, 10-20, 10-25.6, . . . , 10-500.
  • the lower bound of the sub-range would be 45.3
  • the upper bound could be any value from 45.3 to 500, thus yielding sub-ranges such as 45.3-45.3, 45.3-45.4, 45.3-46.5, . . . , 45.3-500.
  • a range from n to (n+i) where n ⁇ x ⁇ R
  • 2 ⁇ x ⁇ 450 ⁇ , and i ⁇ y ⁇ R
  • 0 ⁇ y ⁇ (450 ⁇ n) ⁇ , would encompass all values ranging from greater than 2 up to and including 450, and additionally all sub-ranges within the range of 2 to 450.
  • Any sub-range lower bound may be chosen subject to the constraints.
  • the lower bound of the sub-range would be 10
  • the upper bound could be any value from 10 to 450, thus yielding sub-ranges such as 10-10, 10-10.5, 10-20, 10-25.6, . . . , 10-450.
  • the lower bound of the sub-range would be 45.3
  • the upper bound could be any value from 45.3 to 450, thus yielding sub-ranges such as 45.3-45.3, 45.3-45.4, 45.3-46.5, . . . , 45.3-450.
  • a range from n to (n+i) where n ⁇ x ⁇ R
  • 2 ⁇ x ⁇ 450 ⁇ , and i ⁇ y ⁇ R
  • 0 ⁇ y ⁇ (450 ⁇ n) ⁇ , would encompass all values ranging from 2 up to and including 450, and additionally all sub-ranges within the range of 2 to 450.
  • Any sub-range lower bound may be chosen subject to the constraints.
  • Rates of administration of a natriuretic peptide or other material can be expressed as an absolute rate of a weight or mole amount of the peptide per unit of time or as a weight-based rate that varies based on a subject's weight.
  • 10 ng/kg ⁇ min means that 10 ng of a chimeric natriuretic peptide is administered to the subject every minute for every kg of body weight of the subject.
  • an 85-kg subject receiving a weight-based dose of 10 ng/kg ⁇ min receives 850 ng/min of the natriuretic peptide or an absolute rate of 51 ⁇ g/hr of the natriuretic peptide.
  • the units ng/kg ⁇ min, ng/(kg ⁇ min), ng kg ⁇ 1 min ⁇ 1 and ng/kg/min are equivalent and have the same meaning as described herein.
  • Natriuretic peptides are a family of peptides having a 17 amino acid disulphide ring structure acting in the body to oppose the activity of the renin-angiotensin system.
  • the natriuretic peptides have been the focus of intense study subsequent to the seminal work by DeBold et al. on the potent diuretic and natriuretic properties of atrial extracts and its precursors in atrial tissues (A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats, Life Sci., 1981; 28(1): 89-94).
  • Atrial natriuretic peptide of myocardial cell origin
  • CNP C-type natriuretic peptide
  • BNP brain natriuretic peptide
  • UOD urodilatin
  • Atrial natriuretic peptide ANP
  • ANF atrial natriuretic factor
  • ANP leads to the excretion of sodium and water by the kidneys and to a decrease in intravascular volume and blood pressure.
  • Brain natriuretic peptide (BNP) also originates from myocardial cells and circulates in human plasma similar to ANP.
  • BNP is natriuretic, renin inhibiting, vasodilating, and lusitropic.
  • C-type natriuretic peptide (CNP) is of endothelial cell origin and functions as a vasodilating and growth-inhibiting polypeptide. Natriuretic peptides have also been isolated from a range of other vertebrates.
  • Dendroaspis angusticeps natriuretic peptide is detected in the venom of Dendroaspis angusticeps (the green mamba snake); CNP analogues are cloned from the venom glands of snakes of the Crotalinae subfamily; Pseudocerastes persicus natriuretic peptide is isolated from the venom of the Egyptian snake ( Pseudocerastes persicus ), and three natriuretic-like peptides (TNP-a, TNP-b, and TNP-c) are isolated from the venom of the Inland Taipan ( Oxyuranus microlepidotus ).
  • natriuretic peptides Because of the capacity of natriuretic peptides to restore hemodynamic balance and fluid homeostasis, they can be used to manage cardiopulmonary and renal symptoms of cardiac disease due to its vasodilator, natriuretic and diuretic properties.
  • ANP atrial long-acting natriuretic peptide
  • KP kaliuretic peptide
  • UOD urodilatin
  • ANP atrial natriuretic peptide
  • VD vessel dilator
  • Atrial natriuretic peptide (ANP) has been implicated in diseases and disorders involving volume regulation, such as congestive heart failure, hypertension, liver disease, nephrotic syndrome, and acute and chronic renal failure.
  • ANP has growth regulatory properties in blood vessels that inhibit smooth muscle cell proliferation (hyperplasia) as well as smooth muscle cell growth (hypertrophy). ANP also has growth regulatory properties in a variety of other tissues, including brain, bone, myocytes, red blood cell precursors, and endothelial cells. In the kidneys, ANP causes antimitogenic and antiproliferative effects in glomerular mesangial cells. ANP has been infused intravenously to treat hypertension, heart disease, acute renal failure and edema, and shown to increase the glomerular filtration rate (GFR) and filtration fraction.
  • GFR glomerular filtration rate
  • ANP has further been shown to reduce proximal tubule sodium ion concentration and water reabsorption, inhibit net sodium ion reabsorption and water reabsorption in the collecting duct, lower plasma renin concentration, and inhibit aldosterone secretion. Further, administration of ANP has resulted in mean arterial pressure reduction.
  • ANP prohormone Within the 126 amino acid (a.a.) ANP prohormone are four peptide hormones: long acting natriuretic peptide (LANP) (also known as proANP 1-30) (a.a. 1-30), vessel dilator. (VD) (a.a. 31-67), kaliuretic peptide (KP) (a.a. 79-89), and atrial natriuretic peptide (ANP) (a.a. 99-126), whose main known biologic properties are blood pressure regulation and maintenance of plasma volume in animals and humans.
  • LTP long acting natriuretic peptide
  • VD vessel dilator.
  • KP kaliuretic peptide
  • ANP atrial natriuretic peptide
  • the peptide sequences for these four ANP peptide hormones are as follows:
  • proANP or LAND (a.a. 1-30) (SEQ ID No. 1) NPMYNAVSNADLMDFKNLLDHLEEKMPLED Vessel Dilator, (a.a. 31-67) (SEQ ID No. 2) EVVPPQVLSEPNEEAGAALSPLPEVPPWTGEVSPAQR Kaliuretic Peptide, (a.a. 79-98) (SEQ ID No. 3) SSDRSALLKSKLRALLTAPR ANP, (a.a. 99-126) (SEQ ID No. 4) SLRRSSCFGGRMDRIGAQSGLGCNSFRY
  • the fifth member of the atrial natriuretic peptide family is isolated from human urine and has an N-terminal extension of four additional amino acids, as compared with the circulating form of ANP (a.a. 99-126). This hormone is synthesized in the kidney and exerts potent paracrine renal effects.
  • Urinary and plasma urodilatin mearured by a direct RIA using a highly specific antiserum Clin. Chem., 1998; 44(12):2524-2529.
  • the peptide sequence for BNP is as follows:
  • ANP hormones in diseases and disorders involving volume regulation, such as congestive heart failure, hypertension, liver disease, nephrotic syndrome, and acute and chronic renal failure, has been studied in human and animal models.
  • ANP prohormone is secreted in response to atrial stretch, ANP levels are elevated in patients having congestive heart failure (CHF).
  • CHF congestive heart failure
  • the plasma level of ANP can indicate the severity of CHF, and correlates directly with right atrial and pulmonary capillary wedge pressures and inversely with cardiac index, stroke volume, blood pressure, and New York Heart Association functional class (Brenner et al., Diverse biological actions of atrial natriuretic peptide, Physiol. Rev., 1990; 70(3): 665-699).
  • the systems and methods of the invention are directed to the administration of a natriuretic peptide to a patient for the treatment of Kidney Disease (KD) alone, Heart Failure (HF) alone, or KD with concomitant HF. It is understood that both separate and/or simultaneous treatment of KD and HF is contemplated by the invention.
  • the systems and methods of the invention are also useful for treating other renal or cardiovascular diseases, such as heart failure, dyspnea, elevated pulmonary capillary wedge pressure, chronic renal insufficiency, kidney disease, acute renal failure, cardiorenal syndrome, and diabetes mellitus, any combination of which may be treated simultaneously or separately.
  • the plasma levels of the natriuretic peptides can be increased by causing the selective release of natriuretic peptide using a drug provisioning component.
  • a control consisting of a computer processor unit may also be present that is connected to and in communication with the drug provisioning component.
  • the control unit of the invention contains a set of instructions that causes the drug provisioning component to administer the natriuretic peptide to the patient according to a therapeutic regimen.
  • the therapeutic regimen is tailored so that the plasma concentration of the natriuretic peptide is maintained within a specified range by effecting controlled administration of the natriuretic peptides using the drug provisioning component.
  • This specified concentration is preferably not greater than a plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 6000 ng of the natriuretic peptide per kilogram of the patient's body weight or a level reached by a one hour intravenous infusion of the natriuretic peptide at 100 ng of the natriuretic peptide per kilogram ⁇ minute of the patient's body weight.
  • the drug provisioning component used in the methods of the invention is a continuous infusion apparatus.
  • the continuous infusion apparatus is configured to impact the basal rate of infusion of the therapeutic formulation.
  • the “basal rate” is the continuous infusion rate of the drug that may be programmed.
  • the continuous infusion apparatus preferably administers the natriuretic peptide to the patient subcutaneously and in accordance with the therapeutic regimen.
  • the drug provisioning component may contain an infusion apparatus designed to implement a bolus infusion rate. “Bolus” infusion is a rapid infusion of a drug to expedite the effect rapidly by increasing drug concentration level in the blood.
  • the drug provisioning component may be configured to use both basal rate and bolus rate infusion or to use only one infusion method, either basal rate or bolus.
  • the drug provisioning component may also be configured to deliver a drug in a cyclic on/off or repeating pattern alternating between an “on” and “off” state where the drug is delivered as a set of repetitive doses over duration of time.
  • suitable types of pumps include, but are not limited to, osmotic pumps, interbody pumps, infusion pumps, implantable pumps, peristaltic pumps, other pharmaceutical pumps, or a system administered by insertion of a catheter at or near an intended delivery site, the catheter being operably connected to the pharmaceutical delivery pump.
  • the catheter can be used to directly infuse a kidney via a renal artery catheter.
  • substantially continuous manner means that the dosing rate is constantly greater than zero during the periods of administration.
  • the term includes embodiments when the therapeutic agent is administered at a steady rate, e.g., via a continuous infusion apparatus.
  • the natriuretic peptide may be administered only in a substantially continuous manner throughout the entire treatment period.
  • the contemplated manners of administration may be combined during the same stage or altered during different stages of the treatment.
  • FIG. 2 illustrates a disposable external infusion pump 101 that is attached to the body 105 of a patient.
  • the disposable external infusion pump includes a reservoir that contains the therapeutic formulation, which may comprise the natriuretic peptide.
  • the pump may be operated by the patient, wherein the patient presses a button 102 , which causes the release of a predetermined volume of the drug, and the drug is delivered to the body of the patient via cannula 103 .
  • the tip of the cannula is preferably located subcutaneously.
  • the reservoir may be refilled through a hole 104 .
  • Exemplary methods of the invention further employ a programmable feature.
  • a suitable pump a number of characteristics are considered. These characteristics include, but are not limited to, biocompatibility, reliability, durability, environmental stability, accuracy, delivery scalability, flow delivery (i.e., continuous versus pulse flow), portability, reusability, back pressure range and power consumption. Examples of suitable pumps known in the art are described herein. A person with ordinary skill in the art is capable of selecting an appropriate pump for methods and systems described herein.
  • infusion pump and/or communication options may be of the type described in, but not limited to U.S. Pat. Nos.
  • Examples of external infusion pumps include Medtronic MiniMed® Paradigm® pumps and one example of a suitable implantable pump is Medtronic SynchroMed® pump, all manufactured by Medtronic, Inc., Minneapolis, Minn. Another example of an implantable drug pump is shown in Medtronic, Inc. “SynchroMed® Infusion System” Product Brochure (1995). Additional examples of external infusion pumps include Animas Corporation Animas® and OneTouch® Ping® pumps, manufactured by Animas Corporation, Frazer, Pa.
  • Implantable drug pumps can use a variety of pumping mechanism such as a piston pump, rotary vane pump, osmotic pump, Micro Electro Mechanical Systems (MEMS) pump, diaphragm pump, peristaltic pump, and solenoid piston pump to infuse a drug into a patient.
  • Peristaltic pumps typically operate by a battery powered electric motor that drives peristaltic rollers over a flexible tube having one end coupled to a therapeutic substance reservoir and the other end coupled to an infusion outlet to pump the therapeutic substance from the therapeutic substance reservoir through the infusion outlet.
  • Examples of solenoid pumps are shown in U.S. Pat. No. 4,883,467 “Reciprocating Pump For An Implantable Medication Dosage Device” to Franetzki et al. (Nov.
  • the continuous infusion device used in the methods of the invention has the desirable characteristics that are found, for example, in pumps produced and sold by Medtronic, such as Medtronic MiniMed® Paradigm® models.
  • the Paradigm® pumps include a small, wearable control unit, which enables patients to program the delivery of the therapeutic agent via inputs and a display.
  • the pump control unit includes microprocessors and software which facilitate delivery of the therapeutic agent fed from an included reservoir by a piston rod drive system.
  • the pumps also include wireless telemetry for continuous system monitoring based on data obtained from optional sensors.
  • continuous administration can be accomplished by, for example, another device known in the art, such as a pulsatile electronic syringe driver (e.g., Provider Model PA 3000, Pancretec Inc., San Diego Calif.), a portable syringe pump such as the Graseby model MS16A (Graseby Medical Ltd., Watford, Hertfordshire, England), or a constant infusion pump such as the Disetronic Model Panomat C-S Osmotic pumps, such as that available from Alza, a division of Johnson & Johnson, may also be used. Since use of continuous subcutaneous injections allows the patient to be ambulatory, it is typically chosen over continuous intravenous injections.
  • a pulsatile electronic syringe driver e.g., Provider Model PA 3000, Pancretec Inc., San Diego Calif.
  • a portable syringe pump such as the Graseby model MS16A (Graseby Medical Ltd., Watford, Hertfordshire, England)
  • External infusion pumps for use in embodiments of the invention can be designed to be compact (e.g., less than 15 cm ⁇ 15 cm) as well as water resistant, and may thus be adapted to be carried by the user, for example, by means of a belt clip.
  • Examples of external pump type delivery devices are described in U.S. patent application Ser. No. 11/211,095, filed Aug. 23, 2005, titled “Infusion Device And Method With Disposable Portion” and Published PCT Application No. WO 2001/70307 (PCT/US01/09139), titled “Exchangeable Electronic Cards For Infusion Devices” (each of which is owned by the assignee of the present invention), Published PCT Application No.
  • WO 2004/030716 (PCT/US2003/028769), titled “Components And Methods For Patient Infusion Device,” Published PCT Application No. WO 04/030717 (PCT/US2003/029019), titled “Dispenser Components And Methods For Infusion Device,” U.S. Patent Application Publication No. 2005/0065760, titled “Method For Advising Patients Concerning Doses Of Insulin,” and U.S. Pat. No. 6,589,229 titled “Wearable Self-Contained Drug Infusion Device,” each of which is incorporated herein by reference in its entirety.
  • the present invention contemplates the aforementioned pumps adapted for use in delivering the compositions of the invention.
  • the pump includes an interface that facilitates the portability of the pump (e.g., by facilitating coupling to an ambulatory user).
  • Typical interfaces include a clip, a strap, a clamp or a tape.
  • the infusion pump includes a control module connected to a fluid reservoir or an enclosed fluid reservoir may be disposed within the pump.
  • the control module can include a pump mechanism for pumping fluid from the fluid reservoir to the patient.
  • the control module includes a control system including a pump application program for providing a desired therapy and patient specific settings accessed by the pump application program to deliver the particular therapy desired to the patient.
  • the control system can optionally be connected or coupled or directly joined to a network element, node or feature that is communication with a database.
  • a communications port is provided to transfer information to and from the drug pump.
  • Other embodiments include a wireless monitor and connections as described in U.S. Patent App. Pub. No. 2010/0010330, the contents of which are incorporated herein by their entirety.
  • the pump can further be programmable to allow for different pump application programs for pumping different therapies to a patient as described herein.
  • the drug delivery or infusion pump of the present invention is implanted subcutaneously and consists of a pump unit with a drug reservoir and a flexible catheter through which the drug is delivered to the target tissue.
  • the pump stores and releases prescribed amounts of medication via the catheter to achieve therapeutic drug levels either locally or systemically (depending upon the application).
  • the center of the pump has a self-sealing access port covered by a septum such that a needle can be inserted percutaneously (through both the skin and the septum) to refill the pump with medication as required.
  • the continuous pumps of the invention can be powered by gas or other driving means and can be designed to dispense drugs under pressure as a continual dosage at a preprogrammed, constant rate.
  • the amount and rate of drug flow are regulated by the length of the catheter used, temperature, and are best implemented when unchanging, long-term drug delivery is required.
  • the pumps of the invention preferably have few moving parts and require low power.
  • Programmable pumps utilizing a battery-powered pump and a constant pressure reservoir to deliver drugs on a periodic basis can be programmed by the physician or by the patient.
  • the drug may be delivered in small, discrete doses based on a programmed regimen, which can be altered according to an individual's clinical response.
  • Programmable drug delivery pumps may be in communication with an external transmitter, which programs the prescribed dosing regimen, including the rate, time and amount of each dose, via low-frequency waves that are transmitted through the skin.
  • the infusion pump adjusts the infusion rate according to blood pressure measured by a non-invasive blood pressure measurement device and/or measured body weight.
  • the therapeutic agent can be pumped from a pump chamber and into a drug delivery device, which directs the therapeutic agent to the target site.
  • the rate of delivery of the therapeutic agent from the pump is typically controlled by a processor according to instructions received from the programmer. This allows the pump to be used to deliver similar or different amounts of the therapeutic agent continuously, at specific times, or at set intervals between deliveries, thereby controlling the release rates to correspond with the desired targeted release rates.
  • the pump is programmed to deliver a continuous or intermittent dose of a natriuretic peptide to prevent, or at least to minimize, fluctuations in natriuretic peptide serum or plasma level concentrations.
  • the implantable infusion pump can be configured or programmed to deliver the natriuretic peptide in a constant, regulated manner for extended periods to avoid undesirable variations in blood-level drug concentrations associated with intermittent systemic dosing. It is understood that constant and continuous dosing can lead to better symptom control and superior disease management, particularly in the case of sustained plasma concentration of a natriuretic peptide at a desired level.
  • Other contemplated routes of delivery of the therapeutic agent include intramuscular, parenteral, intraperitoneal, transdermal, or systemic delivery.
  • a drug delivery device may be connected to the pump and tunneled under the skin to the intended delivery site in the body.
  • a pump can be distinguished from other diffusion-based systems in that the primary driving force for delivery by pump is pressure difference rather than concentration difference of the drug between the therapeutic formulation and the surroundings.
  • the pressure difference can be generated by pressurizing a drug reservoir, by osmotic action, or by direct mechanical actuation as described by U.S. Pat. App. Pub. 2009/0281528, and U.S. Pat. Nos. 6,629,954; and 6,800,071, all of which are incorporated herein by reference.
  • the drug provisioning component can be a vascular access port for infusing the drug into patient.
  • the vascular access port can be positioned subcutaneously underneath the skin, or percutaneously when the access part of the port is placed above the level of the skin.
  • the drug provisioning component is a direct delivery catheter system chronically inserted through a small incision into a vessel to deliver the natriuretic peptides of the invention. The surgical procedures to provide for such access are described in the art, for example, in U.S. Pat. App. Pub. 2010/0298901, the contents of which are incorporated herein by reference.
  • an implantable drug delivery device or pump depends upon the device, particularly the catheter, being able to effectively maintain intimate anatomical contact with the target tissue (e.g., the subdural space in the spinal cord, the arterial lumen, the peritoneum) and not become encapsulated or obstructed by scar tissue.
  • the target tissue e.g., the subdural space in the spinal cord, the arterial lumen, the peritoneum
  • these devices are implanted in the body, they are subject to a “foreign body” response from the surrounding host tissues.
  • the body recognizes the implanted device as foreign, which triggers an inflammatory response followed by encapsulation of the implant with fibrous connective tissue.
  • Scarring i.e., fibrosis
  • the present invention contemplates biocompatible coatings being disposed on the surface of the device to prevent or minimize undesirable scarring and inflammation. Such coatings are known in the art and can be employed in the present invention.
  • IM intramuscular
  • SQ subcutaneous
  • IM administration the therapeutic agent is injected deep into skeletal muscle.
  • IM administration is often preferred because of the sustained action it provides as compared to intravenous (IV) administration.
  • SQ administration the therapeutic agent is administered beneath the skin and into subcutaneous tissue.
  • the absorption rate from SQ delivery is slower than from the intramuscular site.
  • tissue sites might be changed frequently to avoid local tissue damage and accumulation of unabsorbed drug.
  • SQ delivery often lowers the potency of a peptide or protein drug due to degradation or incomplete absorption.
  • SQ delivery of a peptide or protein drug is one preferred embodiment, depending on the particular effect desired and the rate of absorption and/or degradation at the delivery site. Further, SQ delivery can have the benefit of achieving prolonged therapeutic effect.
  • the pharmacokinetic studies used to assess the systemic exposure of administered drugs and factors likely to affect this exposure are to be conducted as outlined herein.
  • Known methods of obtaining pharmacokinetic data require time consuming laboratory experiments, and is intended to provide a clear and consistent picture from which accurate conclusions can be drawn.
  • the study of the invention is designed to isolate a single variable and use a placebo control group as a baseline from which the variable is measured. Observations from the trial are used to formulate conclusions from apparent differences between the control group and the test group. Given the complex and dynamic nature of the study, the results thereof are unexpected.
  • the statistical analysis of pharmacokinetic data of the study addresses time-dependent repeated measurements of drug of concentrations in various organs of the body, with the goal being to describe the time course and to determine clinically relevant parameters by modeling the organism through compartments and flow rates.
  • the mathematical solution is a system of differential equations with an explicit solution for most of the one or two compartment models.
  • Intrinsic pharmacokinetic parameters include area under the curve (AUC), clearance, distribution volume, half-time or half-life, elimination rates, minimum inhibitory concentrations, etc.
  • AUC area under the curve
  • clearance measures the body's ability to eliminate a drug. It does not indicate how much drug is removed, but rather the volume of blood or plasma that would be completely cleared of the drug. Thus, clearance is expressed as a volume per unit time, or flow parameter.
  • 0 ⁇ x ⁇ 60 ⁇ and i ⁇ y ⁇
  • x 20
  • the lower bound of the range is 20 ng/ml
  • the upper bound is from 20 to 60 ng/ml
  • i ranges from 0 to 20 ng/ml, so that the following ranges of concentration values are provided: 20 ng/ml, 20-21, 20-22, 20-23, . . . , 20-60 ng/ml.
  • the plasma concentration values may be in the following non-limiting ranges from about 1-1, 1-2 ng/ml, 1-5, 1-10, 5-10, 10-20, 10-30, 10-60, 20-60, etc., and that any value from greater than 0 to 60 ng/ml is contemplated by the invention.
  • 0 ⁇ x ⁇ 40 ⁇ and i ⁇ y ⁇
  • 0 ⁇ x ⁇ 20 ⁇ , and i ⁇ y ⁇
  • the natriuretic peptides can be subcutaneously infused at a dose to maintain a plasma level that is not greater than the plasma level reached during either the subcutaneous bolus or 1 hour IV infusion determinable by patient body weight.
  • the pharmacokinetic model of the vessel dilator peptide for an 85 kg subject is shown in FIG. 1 .
  • FIG. 1 shows the pharmacokinetic model of the subcutaneous injection as compared to an estimated model of the equivalent IV dosage.
  • the peak concentration reached in the plasma is slightly higher in the IV infusion model, but the area under the curve for the two methods of delivery are similar.
  • an 85 kg subject receiving a bolus dose of 0.51 mg would reach a peak plasma level from about 8 ⁇ g/L.
  • a continuous infusion from about 200 ⁇ g/hr is calculated to lead to steady state concentrations of about 7.8 ⁇ g/L.
  • the area under the curve (AUC) calculation shows that the total AUC on a daily basis is about 5 times as large as for the single bolus injection, but the peak height (Cmax) is the same as the bolus injection and IV infusion.
  • the rate of administration contemplated by the invention is in the range from 10 to 150 ng/kg ⁇ min, such as 10 ng/kg ⁇ min, 10-125, 20-125, and 50-125 ng/kg ⁇ min.
  • 10 ⁇ x ⁇ 300 ⁇ , and i ⁇ y ⁇
  • 10 ⁇ x ⁇ 150 ⁇ , and i ⁇ y ⁇
  • the atrial natriuretic peptides can be subcutaneously infused for 4 hours on and 8 hours off, repeating for 3 days, at rates corresponding to the same Cmax as observed in the first study. This can generate an AUC that is approximately two times that of the single bolus injection but is comparable to an IV infusion AUC, considering that the IV infusion is to be given at 12 hour intervals.
  • dosing can occur continuously at a rate that would match the AUC of a bolus subcutaneous injection. This can be accomplished where the total amount of natriuretic peptide infused can be reduced or the time frame can be limited similar to the second scenario. If infusion is performed continuously while maintaining the AUC of the single bolus injection, then it may only be possible to achieve steady state levels of the peptide of between 1 and 1.5 ⁇ g/L. It is expected that this level will produce only minimal biological efficacy. Alternatively, infusion may be performed for 2 hours on then 10 hours off, or following a similar schedule.
  • the method may further comprise monitoring one or more physiologic parameters of the patient.
  • the method further comprises creating a patient-specific dose-response database using data collected from the patient, evaluating the data in the database to maintain a plasma level of the natriuretic peptide in the patient within a specified mean steady state concentration range, and continuously monitoring patient data and updating the instructions, if necessary.
  • the monitoring means and control elements can be in communication with the drug provisioning component to provide instructions as needed to either deliver drug.
  • a control module that controls or provides controlling instructions to the pump can be configured for use in the invention.
  • the control module can adjust a dosing schedule and/or calculate a new dosing schedule using signals from the patient.
  • a control module includes an outer housing containing within the control system and pump mechanism with an input module to permit entry of information into the pump.
  • the control module can further contain a communications port to allow communication with pump from an external device located either locally or remotely relative to pump.
  • An external power supply port allows for connection of an external power supply to operate pump, or, in the case of an implantable pump, a receiver that can convert radio waves into power and store the received energy into a capacitor, and then perform a voltage boost to supply the system components with a regulated voltage.
  • memory configured either internally or externally can store various programs and data related to the operation of the pump.
  • the memory is coupled to microprocessor, which, in turn, runs the desired operating programs which control operation of pump mechanism. Access to the microprocessor is provided through communications port or by other communication links such as infrared telemetry.
  • Information programmed into memory instructs information to be transmitted or received via communications port or via infrared telemetry or other wireless means know to those of skill in the art. This feature allows information being received via communications port from an external device to control pump. This feature also allows for the downloading of any or all information from memory to an external device.
  • the control unit of the medical system of the invention can regulate the selective release of the natriuretic peptide to maintain a mean steady state concentration using data obtained from the patient.
  • the control unit may further contain computer memory, and the control unit, using the computer memory and processor, may further compile and store a database containing data collected from the patient and also compute a dosing schedule that makes up a part of the therapeutic regimen.
  • Calculating dosing instructions used in the methods and systems described herein may consist of administering a test dose of the natriuretic peptide to the patient and then observing a concentration of circulating natriuretic peptide in the serum of the patient that results from the test dose. The concentration is then used to design a patient-specific therapeutic regimen that includes administering the natriuretic peptide to the patient subcutaneously using a continuous infusion apparatus in an amount sufficient to maintain circulating levels of the natriuretic peptide in the desired range for in vivo concentration for a specific period of time.
  • One illustrative embodiment of the invention includes a method of using a patient-specific regimen responsiveness profile obtained from a patient having kidney disease alone, heart failure alone, or kidney disease with concomitant heart failure to design a patient-specific therapeutic regimen.
  • Embodiments of this method comprise administering at least one therapeutic agent, e.g., a natriuretic peptide, to the patient as a test dose (optionally, a dose that is a part of a first therapeutic regimen) and then obtaining pharmacokinetic or pharmacodynamic parameters from the patient to observe a patient-specific response to the test dose.
  • a therapeutic agent e.g., a natriuretic peptide
  • pharmacokinetic or pharmacodynamic parameters obtained consist of a concentration of the natriuretic peptide in the plasma of the patient that results from the test dose.
  • practitioners can then use the pharmacokinetic or pharmacodynamic parameters obtained to observe a patient-specific response to the test dose, and the observed response is then used to create a patient-specific regimen responsiveness profile.
  • This profile necessarily takes into account a variety of physiologic parameters observed in the patient.
  • the patient-specific regimen responsiveness profile is then used to design a patent-specific therapeutic regimen. Once a therapeutic regimen is selected and administered, practitioners can then obtain or modify a patient-specific regimen responsiveness profile that results from the administration of this therapeutic regimen.
  • the patient-specific regimen responsiveness profile can then be used to design further patient-specific therapeutic regimens.
  • the therapeutic regimen calculated using the systems and methods of the invention may be based on any relevant biological parameter, such as the body weight of a patient.
  • the features illustrated or described as being part of one embodiment may be used on another embodiment to yield a still further embodiment.
  • IV Intravenous
  • VD Vessel Dilator
  • VD vessel dilator
  • IV intravenous
  • the half life of the VD peptide for this route of administration is estimated to be about 20 minutes.
  • Subjects are divided into two dose groups: (1) 50 ng/kg ⁇ min infusion rate and (2) 100 ng/kg-min infusion rate.
  • the total dose delivered at 50 ng/kg ⁇ min is 255 ⁇ g, and at 100 ng/kg ⁇ min, the total dose delivered is 510 ⁇ g.
  • the pharmacokinetic model for this IV infusion is shown in FIG. 3 .
  • the peak plasma levels reached are 17.7 and 35.5 ng/ml for the 50 and 100 ng/kg-min doses, respectively.
  • Administration of the peptide can be varied to achieve different models of exposure of the patient to the peptide.
  • an 85 kg subject can receive a bolus dose of peptide to reach a peak plasma level of about 8 ⁇ g/L.
  • an 85 kg subject can receive a continuous infusion over a daily period of 200 ⁇ g/hr to achieve a comparable peak plasma level of about 7.8 ⁇ g/L.
  • continuous infusion over the course of a day period will result in a total exposure of the peptide (i.e., AUC) of about 5 times the level a single bolus injection of 0.51 mg of peptide.
  • the 85 kg subject has a half-life for subcutaneous absorption for the peptide of 20 minutes and a half-life for elimination of the peptide of 2 hours along with a distribution of the peptide in a volume equivalent to 60% of body weight.
  • Subjects can vary in the absorption parameters in particular.
  • a subject can exhibit a half-life for absorption from 0 to 60 minutes depending upon the physiological state of the subject.
  • 0 ⁇ x ⁇ (60 ⁇ n) ⁇ , and i ⁇ y ⁇
  • a subject can exhibit a half-life for subcutaneous absorption of the peptide from 0 to about 30 minutes, from 0 to about 5 minutes, from about 15 to 25 minutes, and from about 15 to about 30 minutes, in addition to about 20 minutes.
  • Subjects can further vary in elimination parameters for removal of the peptide, depending upon the physiological state of the patient and other additional parameters.
  • a subject can exhibit a half-life for elimination of the peptide from about 20 minutes to about 4 hours, from about 20 minutes to about 1 hour, from about 30 minutes to about 1.25 hours, from about 1 to about 3 hours or from about 20 minutes to 40 minutes.
  • 5 ⁇ x ⁇ 240 ⁇ and i ⁇ y ⁇
  • An administration of the peptide can be performed to achieve similar peak plasma levels while limiting the total exposure of the peptide to the subject.
  • a subcutaneous infusion can be performed over the course of 4 hours, followed by an 8 hour off period, and then followed by an additional 4 hours of subcutaneous infusion. This cycle can be repeated during the course of treatment.
  • a peak plasma concentration of about 8 ⁇ g/L can be reached.
  • the total exposure of the peptide to the subject i.e., AUC
  • the total exposure of the peptide to the subject i.e., AUC
  • AUC the total exposure of the peptide to the subject
  • the total exposure of the subject to the peptide by subcutaneous infusion can be maintained at a level equivalent to a subcutaneous single bolus injection with 0.51 mg peptide.
  • the total exposure to the subject can be limited to the same AUC as for a single bolus injection of 0.51 mg for the above-described 85 kg subject over a daily period of infusion treatment.
  • the subject can be infused to achieve a higher peak plasma concentration with extended off periods to limit AUC.
  • the subject can be infusion for 2 hour periods with intervening 10 hour off periods. Other lengths of infusion periods and off periods are possible to achieve desired characteristics.
  • the half-life for elimination of the peptide can have a noticeable effect on the pharmacokinetics exhibited for the peptides described herein. As discussed above, a subject can exhibit a half-life for elimination falling into one of several ranges. Half-life for elimination is believed to be impacted by the physiological state of the subject. This includes not only the weight, age, water-retention of the subject, but also the presence of specific disease states, including impairment of kidney function.
  • 0 ⁇ x ⁇ 60 ⁇ and i ⁇ y ⁇
  • a subject has a glomerular filtration rate less than about 15 mL/min/1.73 m 2 or in the range from 0 to about 60 mL/min/1.73 m 2 .
  • kidney disease may sometimes unexpectedly display a shorter half-life for elimination of natriuretic peptides compared to individuals not having kidney disease. That is, it is expected that subjects having kidney disease would have a longer half-life for elimination of the peptide compared with the average healthy individual not displaying impairment of kidney function.
  • the steady state plasma concentration achieved by infusion of the peptide by subcutaneous infusion is from about 20 to about 40 ⁇ g/L, as previously described. In certain other embodiments, the steady state plasma concentration achieved by subcutaneous infusion can be from about 10 to about 60 ⁇ g/L, about 10 to about 20 ⁇ g/L, from about 20 to about 30 ⁇ g/L, from about 20 to about 35 ⁇ g/L, from about 25 to about 40 ⁇ g/L, from about 30 to about 40 ⁇ g/L or from about 5 to about 40 ⁇ g/L.
  • the steady state plasma concentration achieved by subcutaneous infusion can be from about 0 to about 40 ⁇ g/L, from about 0.5 to about 40 ⁇ g/L, from about 2 to about 40 ⁇ g/L or from about 5 to about 40 ⁇ g/L.
  • the steady state plasma concentration achieved by infusion is influenced by the rate of infusion or dosing administered to the subject.
  • the peptide is administered by infusion at a rate from about 10 to about 150 ng/kg ⁇ min based upon the subject's body weight.
  • the peptide is administered by infusion at a rate from about 10 to about 300 ng/kg ⁇ min, about 20 to about 125 ng/kg ⁇ min, from about 50 to about 125 ng/kg ⁇ min, from about 90 to about 110 ng/kg ⁇ min in addition to about 95 to about 100 ng/kg ⁇ min.
  • the peptide is administered by infusion at a rate of infusion based upon subject's weight from about 10 to 300 ng/kg ⁇ min, from about 10 to 250 ng/kg ⁇ min, or from about 10 to about 200 ng/kg ⁇ min.
  • the natriuretic peptide is administered to the subject at a rate from any one of about 25 to about 145 ng/kg ⁇ min, about 30 to about 140 ng/kg ⁇ min, about 35 to about 125 ng/kg ⁇ min, about 50 to about 120 ng/kg ⁇ min, about 65 to about 115 ng/kg ⁇ min, and about 85 to about 110 ng/kg ⁇ min of the subject's body weight.
  • One of the factors affecting the amount of peptide infused into the subject is the subject's body weight.
  • weight is not the only factor affecting the amount of peptide administered by infusion.
  • the subject's physiological state also influences the amount of peptide required.
  • subjects typically require a subcutaneous infusion dose from about 51 to about 765 ⁇ g/hr in certain embodiments.
  • a subject can require a subcutaneous infusion dose from about 75 to about 500 ⁇ g/hr, from about 100 to about 500 ⁇ g/hr or from about 125 to 450 ⁇ g/hr.
  • from about 0.6 to about 9 ⁇ g of the natriuretic peptide is administered to the subject per kg of the subject's body weight in an hour time period.
  • the natriuretic peptide is administered to the subject at a rate from about 1 to about 8 ⁇ g, from about 2 to about 5 ⁇ g, from about 3 to about 4 ⁇ g, from about 1 to about 7 ⁇ g, from about 3 to about 5 ⁇ g, from about 2 to about 6 ⁇ g, from about 7 to about 9 ⁇ g, or from about 8 to about 9 ⁇ g of the natriuretic peptide per kg of the subject's body weight in an hour time period.
  • VD Vessel Dilator
  • a two-part study can be performed to determine the pharmacokinetics of subcutaneously delivered Vessel Dilator (VD) peptide and to establish a relationship between the pharmacokinetics of VD and the subsequent pharmacodynamics, particularly related to hemodynamics and kidney function.
  • VD Vessel Dilator
  • a number of subjects can be dosed subcutaneously with VD.
  • a full range of noninvasive measurements can be obtained.
  • the first study can thereby result in establishing pharmacokinetic parameters in the subjects at certain doses.
  • a second part of the study can be run on 16 subjects, all of whom are fitted with right heart catheters to measure hemodynamics. This stage can be run in two doses.
  • the nominal doses can be chosen to mimic the peak plasma levels reached by IV infusion and subcutaneous (SQ) bolus administration of the first part of the study described herein.
  • a first group of 8 subjects within the second part can be dosed at 250 ⁇ g/hour for 6 hours. This can lead to a steady state plasma concentration of about 10.0 ng/ml, which can be less than the peaks reached in either an IV infusion or SQ bolus study.
  • a second set of 8 subjects in the second part of the study can be tested using a dose of 500 ⁇ g/hour for 6 hours.
  • the second part can begin.
  • the delay between the first and second parts should be no longer than one month.
  • Up to 18 subjects can be enrolled in the study, where the subjects can be divided into two groups with a goal of at least 8 evaluable subjects in each group.
  • the first 8 subjects can be dosed for 6-12 hours by SQ infusion with VD peptide at a rate that will lead to a plasma concentration of 10 ng/mL above baseline, which is about half of the peak plasma concentration reached during a 1 hr IV infusion at 50 ng/kg ⁇ min.
  • a second set of subjects can receive a higher dose for 6-12 hours by SQ infusion at a rate sufficient to result in a steady state plasma concentration of 20 ng/mL, which is about half of the peak plasma concentration reached during a 1 hr IV infusion at 100 ng/kg ⁇ min.
  • VD peptide is a natural hormone peptide derived from ANP, as discussed above.
  • subjects are expected to have a baseline endogenous plasma concentration of VD peptide.
  • Administration of VD peptide by SQ infusion will increase the levels above the endogenous background level of VD in the subjects.
  • the plasma concentrations for VD of 10 and 20 ng/mL are plasma concentrations reached in addition to the endogenous baseline concentration of VD in a particular subject.
  • background plasma concentrations of VD peptide in heart failure patients are near 5 ng/ml.
  • concentrations significantly higher than these are measured, for example, baseline plasma concentrations of VD peptide for NYHA class IV patients and can be approximately 20 ng/ml.
  • the VD peptide will be administered by SQ infusion in sterile Elliott's Buffer B at 1 mg/ml using a Medtronic MiniMed ParadigmTM infusion pump system (Elliott's Buffer: 7300 mg NaCl, 1900 mg sodium bicarbonate, 800 mg dextrose, 300 mg MgSO 4 .7H 2 O, 300 mg KCl, 200 mg CaCl 2 .2H 2 O and 200 mg sodium phosphate dibasic.7H 2 O per liter). All patients in the study can have GFR measured during the week prior to a clinic visit for the SQ administration of VD. Prior to administration of VD, routine laboratory measurements as well as non-invasive hemodynamics can be observed including estimates of ejection fraction by magnetic resonance imaging (MRI) and/or echocardiogram. Subject selection criteria are shown in Table 2.
  • MRI magnetic resonance imaging
  • Inclusion Criteria a) Patients with a history of symptomatic congestive heart failure, with a left ventricular ejection fraction of ⁇ 45% measured by echocardiogram or MRI (measurement 3-6 months prior to screening); b) Brain Natriuretic Peptide (BNP) ⁇ 100 pg/mL; c) Signed Consent; d) 18 years or older; e) Non-pregnant females as evidenced by blood test or 2 consecutive urine tests; f) eGFR greater ⁇ 25 ml/min/1.73 m 2 (MDRD method) and less than 70 ml/min/1.73 m 2 ; g) Patients on a stable, background therapeutic doses of a beta-blocker, ACE- inhibitor or ARB, unless contraindicated and documented as such; and h) Patients on a stable, background therapeutic dose of a diuretic and/or aldosterone receptor inhibitor (e.g.
  • MI Myocardial Infarction
  • CK creatinine kinase
  • CK-MB muscle-brain isoenzyme
  • IMVS Institute of Medical and Veterinary Science
  • the primary outcome measurement of the study will be the safety and tolerability of the various doses of VD.
  • Efficacy outcome data to be measured include:
  • CI Change in cardiac index
  • a dosing protocol can be designed. Continuous SQ infusion of VD peptide can be designed to yield steady state plasma concentrations that are less than levels reached during 1-hour IV infusion administrations that are current clinical practice.
  • the SQ infusion protocol for VD peptide will be determined to yield plasma levels of 10 and 20 ng/ml above baseline, as described above. Data that will be obtained from LC-MS or LC-MS-MS assays will be used to calculate the appropriate SQ infusion dosing regimen.
  • the primary safety endpoints are drug related adverse events.
  • the primary efficacy endpoints are changes in GFR as well as changes in blood pressure and cardiac output measured non-invasively.
  • the secondary efficacy endpoints to be analyzed include:
  • FIG. 4 shows a model 85 kg subject having a 60% volume of distribution for the peptide based upon the subject's weight. This 85 kg subject can be dosed by IV infusion over the course of one hour at a rate of 8.5 ⁇ g/min for a total dose of peptide of 0.51 mg. As shown in FIG. 4 , a one hour infusion at this dosing rate is not sufficient to achieve steady state; however, large differences in peak plasma level for the peptide and total exposure of the peptide (AUC) results from changes in half-life for elimination of the peptide. As indicated in FIG.
  • the peak plasma concentration ranges from about 9.2 ⁇ g/L for a subject having a half-life of 4 hours to 7.2 ⁇ g/L for a subject having a half-life of 1 hour.
  • FIG. 4 also shows that the AUC is changed based upon the half-life for elimination of the peptide although the dosing regime is the same for all subjects.
  • FIG. 5 shows that a large change in exposure to the peptide results from subcutaneous bolus injection of the peptide based upon changing half-life for elimination of the peptide.
  • the above-described 85 kg subject as in FIG. 4 is modeled receiving a subcutaneous bolus dose of 0.51 mg of the peptide.
  • the 85 kg subject is modeled as absorbing the single bolus dose instantaneously resulting in the same peak plasma level of the peptide regardless of the half-life for elimination of the peptide.
  • large changes in the AUC and hence the total exposure to the peptide are predicted to occur, although the same single bolus dose is administered with the same maximum plasma level for the peptide.
  • a subject displaying a 4 hour half-life for elimination of the peptide is expected to experience a greater exposure to the peptide compared to a subject displaying a 1 hour half-life due to the presence of elevated plasma levels over an extended period of time.
  • FIG. 6 shows total exposure to the peptide is also predicted to vary depending upon route of administration even if the subject is otherwise identical.
  • FIG. 6 shows the above described 85 kg subject having a 60% volume of distribution based upon the subject's weight.
  • FIG. 6 shows a modeled plasma concentration for the peptide (y-axis) for the 85 kg subject based upon route of administration of a 0.51 mg dose of the peptide for the subject having a half-life for elimination of the peptide of 2 hours.
  • One plot in FIG. 6 models an IV infusion over the course of 1 hour at a rate of 8.5 ⁇ g/min.
  • the other plot in FIG. 6 models a subcutaneous single bolus of 0.51 mg of peptide having instantaneous absorption.
  • the peak plasma levels for the peptide are not largely varied.
  • the AUC for the single bolus injection is about 40% larger than for the one-hour infusion.
  • FIG. 5 demonstrates the change in predicted AUC based upon a single subcutaneous bolus injection having instant absorption depending on the half-life for elimination of the peptide.
  • FIG. 7 shows that the behavior in regarding a change in predicted AUC persists where the single bolus injection is not adsorbed instantaneously.
  • the above described 85 kg subject is modeled having a half-life for absorption of the peptide of 30 minutes.
  • a subject displaying a 4 hour half-life for elimination of the peptide is expected to experience a greater exposure to the peptide compared to a subject displaying a 1 hour half-life due to the presence of elevated plasma levels over an extended period of time.
  • a significant change in peak plasma concentration of peptide is predicted due to the delay in absorption of the peptide into the plasma.
  • FIG. 8 models the above described 85 kg subject having a 60% volume of distribution for the peptide based upon the subject's body weight. The half-life for elimination of peptide exhibited by the subject is fixed at 2 hours. As shown in FIG.
  • a short half-life for absorption (15 minutes) of the peptide results in a peak plasma concentration of about 8 ⁇ g/L.
  • a longer half-life for absorption (45 minutes) of the peptide results in a peak plasma concentration of about 6.2 ⁇ g/L.
  • a change in AUC is observed based upon the peak plasma level for the peptide.
  • FIG. 9 the behavior of the peptide through different routes of administration is compared.
  • the above-described 85 kg subject having a 60% volume of distribution based upon subject weight is modeled in FIG. 9 .
  • the 85 kg subject has a half-life for elimination of the peptide of 2 hours.
  • a total of five curves are modeled in FIG. 9 that vary by route of administration and/or half-life for subcutaneous absorption of the peptide.
  • the 85 kg subject is modeled with either a one hour IV infusion of 0.51 mg of total peptide or a single subcutaneous bolus of 0.51 mg of peptide.
  • the rate of absorption for the single bolus injections is modeled ranging from instantaneous absorption to a half-life for absorption of 30 minutes.
  • the one-hour IV infusion is predicted to have a higher peak plasma level than a subcutaneous bolus having a half-life longer than instantaneous. As such, it is predicted that subcutaneous administration can limit undesirable spikes in peak plasma level while still maintaining a satisfactory AUC for the subject's total exposure to the peptide.
  • FIG. 10 shows the same model plotted with a smaller time scale on the x-axis to show detail.
  • the steady state level of the peptide achieved by subcutaneous infusion can vary depending upon the volume of distribution (VOD) displayed by a particular subject for the peptide.
  • the VOD for particular subjects can vary considerably based upon the particular physiologic condition of the subject. In particular, kidney impairment can have an impact of the VOD displayed by a particular subject.
  • 5 ⁇ x ⁇ 65 ⁇ and i ⁇ y ⁇
  • a subject has a VOD for the peptide from about 10 to about 25 L, from about 5 to about 15 L, from about 30 to about 65 L or from about 45 to about 65 L.
  • 0 ⁇ x ⁇ 137 ⁇ and i ⁇ y ⁇
  • SQ administration of a peptide or protein drug requires satisfactory absorption to obtain a therapeutic effect.
  • SQ administration should demonstrate an ability for the peptide or protein drug to be absorbed through capillary endothelial membranes and cell walls to enter the circulation.
  • VD was administered by SQ infusion to canines to demonstrate the ability of VD to have a pharmacological effect over a long-term course of treatment.
  • VD was administered to canines via a subcutaneous delivery route.
  • the dosing was performed at a high level to assess the toxicity of VD and to determine if a lethal dosing amount of the VD can be reached by subcutaneous administration.
  • VD was administered subcutaneously to canines using a Medtronic Paradigm® infusion pump (model MMT772) over a period of 5 days.
  • VD was obtained as an acetate salt (VD-acetate) from Bachem (lot 2502022) and prepared in Tris/Glycerin/m-cresol buffer at a concentration of 15 mg/mL.
  • the Tris/Glycerin/m-cresol buffer was prepared by mixing 16.0 g glycerol, 6.05 g tris-(hydroxymethyl)-aminomethane (“Tris”), 2.50 g meta cresol in a 1.00 L volumetric flask. Approximately 900 mL nanopure water was added to the volumetric flask and the mixture was magnetically stirred to reach complete dissolution. 4 normal hydrochloric acid was used to adjust pH to 7.3 at 25° C.
  • VD was administered to one male and one female beagle canine at varying dosing amounts. Each canine received a first dosage level for 5 consecutive days followed by a 2-day washout period. Then, the same canines received a second, higher dosage level for an additional 5 consecutive days.
  • the canines Prior to the beginning of dosing with VD (Day 0), the canines were placed in a sling and the dose site on the dorsolateral thorax was shaved. The shaved area was swabbed with 70% isopropyl alcohol and allowed to dry. DuraPrepTM (3M) was then applied and allowed to dry for 3 minutes.
  • the catheter of the infusion set (Medtronic Silhouette Paradigm® Infusion Set MMT-378) was placed subcutaneously and perpendicular to the spine, and attached to the skin. The extension set was then attached to a previously weighed reservoir filled with VD at a concentration of 15 mg/mL in the Tris/Glycerin/m-cresol buffer.
  • the reservoir was inserted into the pump located in a jacket pocket and dosing was commenced. The jacket was then secured and a collar was placed on each canine. Every day during the 5-day period, the reservoirs were exchanged with new filled reservoirs at approximately the same time each day.
  • the infusion sets and jackets were removed, the area where the catheter was placed was marked, and the animals were allowed a 2-day washout period prior to the next treatment.
  • a new infusion site was chosen on the skin, and the pump was prepared as before.
  • the daily dosage level during the first 5-day period was 1.44 mg/(kg ⁇ day) (or 1000 ng/(kg ⁇ min)) for each canine corresponding with a dosage volume of 0.096 ml/(kg ⁇ day).
  • the total dose delivered to each canine over the first 5-day period was 7.20 mg/kg.
  • Canines in Group 1 did not show clinical signs of toxicity during the first 5 days of drug administration.
  • the daily dosage level was increased to 2.88 mg/(kg ⁇ day) (or 2000 ng/(kg ⁇ min)) for each canine corresponding with a dosage volume of 0.192 ml/(kg ⁇ day) during the second 5-day period (Group 2).
  • the total dose delivered to each canine over the second 5-day period was 14.4 mg/kg.
  • the dosing for Group 1 and Group 2 is summarized in Table 3 below.
  • Plasma samples for determination of plasma drug concentration were collected at 2, 4, 24 and 96 hours after the beginning of infusion, immediately prior to the end of infusion on Day 5, and 0.5, 1, 1.5, and 2 hours after the end of dosing.
  • Blood was collected via the jugular vein into chilled tubes containing K 3 -EDTA.
  • Plasma was isolated in a refrigerated centrifuge, placed into prepared tubes containing 1.8 TIU (trypsin inhibitory units) of aprotinin, and stored frozen at approximately ⁇ 70° C. within approximately 1 hour of blood collection. Plasma was analyzed for the concentration of Vessel Dilator using a radioimmunoassay with an approximate lower limit of quantization (LLOQ) of 1 ng/ml.
  • LLOQ lower limit of quantization
  • Subcutaneous administration of VD by constant-rate subcutaneous infusion over each 5-day period resulted in systemic exposure to VD, as measured by AUC ⁇ and C max , that increased proportionally with the increase in dosage from Group 1 to Group 2 for both genders.
  • Exposure was similar between genders, except that T max for both dosages was 120 hours after the start of the infusion for the male canine and about 96 hours after the start of infusion for the female canine.
  • Plasma concentrations of VD fluctuated by approximately 30% for both genders at the 1.44 mg/(kg ⁇ day) dosing rate and by 61% for the male canine and 18.5% for the female canine at the 2.88 mg/(kg ⁇ day) dosing rate.
  • FIG. 11 shows the measured plasma concentrations for VD for both canines at the 7.2 mg/kg dosing ( FIG. 11A ) and the 14.4 mg/kg dosing ( FIG. 11B ).
  • the break in the x-axis on FIG. 11 represents the before- and after-dosing time periods.
  • the pharmacokinetic parameters extracted from the graphs on FIG. 11 are presented below in Table 4. As discussed, T max . (time to highest observed plasma concentration) was at the end of the 5-day dosing periods for the male canine, which implies that plasma concentration was still increasing at the conclusion of dosing. AUC is presented for the 120-hour dosing period (AUC) and including two hours following the stoppage of dosing (AUC last ) in Table 4. Dose normalized AUC ⁇ is shown in FIG. 12A and dose normalized C max is shown in FIG. 12B . Dose normalized parameters are calculated by dividing the parameter by the total dose amount over the 5-day dosing period in units of mg/kg to allow for direct comparison of across dosing amounts.
  • VD was administered to a rat model via a subcutaneous delivery route to assess the toxicity of VD and to determine if a lethal dosing amount of the VD can be reached by subcutaneous administration. As noted above, a maximum tolerated or lethal dosing amount was not observed for canines.
  • VD-acetate (Bachem lot 2502022) was prepared in the Tris/Glycerin/m-cresol buffer at a concentration of 3 mg/mL or 15 mg/mL.
  • the VD solution was administered continuously by subcutaneous infusion using Alzet® (Durect Corp.) osmotic minipumps (model 2002) over a period of 5 days to 3 study groups, where each study group (Groups 1-3) contained 3 male and 3 female Sprague Dawley rats.
  • the continuous subcutaneous delivery dose for Group 1 was calibrated to yield an administration of approximately 100 ng/(kg ⁇ min) of VD, which is in the range of a dosing regimen useful for clinical use in humans.
  • the rats in Group 1 had one Alzet pump implanted with an infusion rate of 0.5 ⁇ l/hour for the 3 mg/mL VD solution, which resulted in actual mean weight-based doses of 0.132 and 0.163 mg/(kg ⁇ day) (or ⁇ 92 ng/(kg ⁇ min) and ⁇ 113 ng/(kg ⁇ min)), for males and females, respectively.
  • the estimated daily dose is reported as 0.144 mg/kg ⁇ day (or 100 ng/(kg ⁇ min)) for all animals in Group 1, and the total dose delivered to each animal over the 5-day period was 0.180 mg.
  • the continuous subcutaneous delivery dose for Group 2 was calibrated to yield an administration of approximately 1000 ng/(kg ⁇ min) of VD, which is 10-fold higher than for Group 1.
  • Each rat in Group 2 each had two Alzet pumps implanted to have a combined infusion rate was 1.0 ⁇ L/hr of the 15 mg/mL VD solution.
  • the resulting actual mean weight-based doses were 1.026 and 1.629 mg/(kg ⁇ day) for males and females, respectively.
  • an estimated body weight of 280 g was used for all animals (males and females); therefore, the estimated daily dose was reported as 1.29 mg/(kg ⁇ day) (or ⁇ 896 ng/(kg ⁇ min)) for all animals in Group 2, and the total dose delivered to each animal over the 5 day period was 1.8 mg.
  • the continuous subcutaneous delivery dose for Group 3 was calibrated to yield an administration of approximately 2000 ng/(kg ⁇ min). Each rat each had four Alzet pumps implanted for a combined infusion rate was 2.0 ⁇ L/hr of the 15 mg/mL VD solution. The resulting actual mean weight-based doses were 1.870 and 3.303 mg/(kg ⁇ day) for males and females, respectively. For pharmacokinetic calculations, an estimated body weight of 300 g was used for all animals (males and females); therefore the estimated daily dose was reported as 2.4 mg/(kg ⁇ day) (or (or ⁇ 1667 ng/(kg ⁇ min)) for all animals in Group 3, and the total dose delivered to each animal for the 5 day period was 3.6 mg.
  • the dosing for Groups 1-3 is summarized in Table 5.
  • All animals in Groups 1-3 were observed twice daily for mortality and moribund appearance during the 5-day dosing period and during an at least 16-day pretest period.
  • Clinical examinations were performed daily for all animals following surgery to implant the Alzet pumps. Detailed physical examinations were conducted on all animals approximately weekly during a pretest period of at least 16 days, prior to beginning dosing (Day 0), and on Day 5 prior to euthanasia.
  • Individual body weights were recorded at least weekly during the pretest period, on Day 0 prior to dosing, and on Day 5 prior to euthanasia.
  • Individual food consumption was recorded approximately weekly during the pretest period, on Day 0 prior to dosing, and on Day 5 prior to euthanasia.
  • Plasma samples for determination of plasma drug concentration were collected from all animals at approximately 4, 8, and 24 hours after pump implantation on Day 0 and immediately prior to euthanasia on Day 5 (120 hours after the start of dosing). Blood was collected via the retro-orbital sinus from animals anesthetized with isoflurane into chilled tubes containing K 3 -EDTA. Following the final blood collection, the animals were euthanized and discarded. Plasma was isolated in a refrigerated centrifuge, placed into prepared tubes containing 0.6 TIU of aprotinin, and stored frozen at approximately ⁇ 70° C. within approximately 1 hour of blood collection. Plasma was analyzed for the concentration of Vessel Dilator using radioimmunoassay with an approximate lower limit of quantization (LLOQ) of 1 ng/ml.
  • LLOQ lower limit of quantization
  • Table 6 summarizes the exposure to VD in terms of C max C avg , and AUC ⁇ as the total dose level is varied from 0.180 to 3.60 mg total dose for the 5-day period.
  • the increase in exposure to VD was generally proportional to the increases in VD dose for both genders. For example, a 20-fold increase in dose (from 0.180 to 3.60 mg over the 5 days) resulted in an increase of approximately 13- to 17-fold for mean AUC ⁇ , C avg , and C max in males and approximately 16- to 18-fold for the same parameters in females.
  • FIG. 13 shows the change in AUC ⁇ ( FIG. 13A ) and C avg ( FIG. 13B ) for male and female in response to increased dose of VD.
  • Tmax The time at which maximum VD plasma concentration occurred (Tmax) could not be determined accurately due to the large sampling intervals.
  • Tables 7 and 8 show the mean measured plasma concentration of VD for male and female rats, respectively. The data for Table 7 and 8 is shown in graphical form in FIGS. 14 and 15 .
  • AUC last AUC ⁇ for all animals. **For T max , range is presented parenthetically. ⁇ For males at 0.180 mg, I sample collected from a male at 120 hours post-dosing (concentration of 180 ng/mL) was a suspected outlier; the mean data excluding this sample are presented in parentheses, except for the range of T max , which was 4-120 hours.
  • VD administered by continuous subcutaneous infusion via Alzet osmotic pumps over a period of 5 days to Sprague Dawley rats at 1.144, 1.29 and 2.4 mg/(kg ⁇ day) was well tolerated at all dosage levels. Due to a lack of any toxicological effects, a maximum tolerated dose was not determined.
  • mean C max values were 431 and 739 ng/ml and mean AUC ⁇ values were 25,789 and 56,956 ng ⁇ hr/mL for males and females, respectively. Normalized by weight, exposure as measured by AUC ⁇ between genders was similar.
  • a pharmaceutical formulation of VD was prepared in a Tris buffer.
  • 16.0 g glycerol, 6.05 g tris-(hydroxymethyl)-aminomethane (“Tris”), 2.50 g meta cresol were mixed in a 1.00 L volumetric flask.
  • Tris tris-(hydroxymethyl)-aminomethane
  • 4 normal hydrochloric acid was used to adjust pH to 7.3 at 25° C.
  • the flask was filled to 1 L mark with nanopure water.
  • the pH was rechecked and verified to be 7.3 at 25° C.
  • the pH 7.3 Tris buffer was stored at 2-8° C. until use.
  • Lyophilized VD peptide (Bachem) was weighted into a glass vial and dissolved into a known volume of the Tris buffer to a concentration between 1 mg/mL and 10 mg/mL. The VD peptide was dissolved by gentle mixing and the solution was allowed to rest for between 20 and 30 minutes. The pH of the solution was checked and adjusted to 7.3 with 0.1 N sodium hydroxide. The solution was filtered through a 0.22 micron sterile filter into a sterile glass vial and stored at 2 to 8° C. until use.
  • the pharmacodynamic effects of VD delivered by subcutaneous infusion were investigated in a canine model high-rate paced (HRP) to a heart rate of 240 bpm (ventricular pacing) over a period of 10 days to simulate HF.
  • HRP high-rate paced
  • the canines were divided into a control group and an experimental group.
  • the control group received a continuous subcutaneous infusion of the Tris buffer without VD over the course of the 10 day period.
  • the experimental group received continuous subcutaneous infusion of VD dissolved in Tris buffer at a dosing rate of 100 ng/kg ⁇ min based upon the body weight of individual canines.
  • each animal received continuous subcutaneous (SQ) infusion of an agent (Tris buffer solution for control animals and vessel dilator in Tris buffer for experimental animals) delivered via external catheter and pump.
  • SQ infusion was performed using Medtronic MiniMed® 407C pumps equipped with 3.0 mL reservoirs (#MMT-103A) and Medtronic Silhouette® combo infusion sets (#MMT373).
  • GFR measurements were repeated on Day 9.
  • HRP On a pre-term monitor was performed for urine and hemodynamic data collection on conscious animals. Once the data was collected, HRP was turned off and the animals were euthanized.
  • FIG. 16 shows the results for GFR measurements taken on Day ⁇ 1 and Day 9 for the control and experimental VD-treated groups.
  • the bar graph shows the average GFR in units of mL/min per kg of body weight with the standard deviation shown by error bars.
  • both the control group canines and the VD experimental group canines had GFR measurements greater than 3 mL/min/kg.
  • the normal range of GFR for canines is shown by the dashed lines in FIG. 16 .
  • the canines in the control group had a GFR less than 2.5 mL/min/kg.
  • the canines in the experimental group receiving VD by SQ infusion also showed a decrease in GFR.
  • the experimental group canines showed an average GFR of close to 3.0 mL/min ⁇ kg, which is within the normal range for canines. As such, the data presented on FIG.
  • FIG. 17 presents the observed change in urine flow in units of ml/min.
  • the change in urine flow is shown on Day 10 with Day 0 serving as the reference baseline.
  • the control group undergoing HRP and receiving SQ infusion of Tris buffer showed a 77% decrease in urine flow on Day 10 compared to the same canines on Day 0.
  • the experimental group receiving SQ infusion of VD showed a 33% decrease in urine flow on Day 10 compared to the same canines on Day 0.
  • the standard deviation for both groups is shown by the error bars on FIG. 17 .
  • a statistical comparison of the control group and experimental group showed a statistically significant difference in urine flow between the control group and the experimental group.
  • An application of the Mann-Whitney rank sum test indicated a p-value of less than 0.05, indicating a statistically significant difference between the control group and the experimental group.
  • An increase in urine flow or a decrease in the rate of urine flow loss is a renal protective effect.
  • FIG. 18 presents the observed change in mean sodium excretion rate in units of mmol/min.
  • the change in sodium excretion rate is shown on Day 10 with Day 0 serving as the reference baseline.
  • the control group undergoing HRP and receiving SQ infusion of Tris buffer showed a 76% decrease in sodium excretion rate on Day 10 compared to the same canines on Day 0.
  • the experimental group receiving SQ infusion of VD showed a 59% decrease in sodium excretion rate on Day 10 compared to the same canines on Day 0.
  • the standard deviation for both groups is shown by the error bars on FIG. 18 .
  • An increase in sodium excretion or a reduction in the decrease in sodium excretion is a renal protective effect.
  • FIGS. 19 and 20 show the mean right atrial pressure and the mean pulmonary capillary wedge pressure, respectively, for the control and experimental groups. The observed standard deviation is indicated by error bars. As shown for the control group at Day 10, the right atrial pressure is significantly elevated in the control dogs compared with either group at Day 0 (p-value ⁇ 0.05). ANOVA and post-hoc test indicates that the increase in right atrial pressure in the control group at Day 10 is statistically significant in comparison with the control and experimental groups at Day 0.
  • a statistically significant change in right atrial pressure is also seen between the control group and the experimental group on Day 10 (p-value ⁇ 0.05).
  • An increase in right atrial pressure as a result of HRP was expected, as shown by the control group on Day 10 where mean pressure increased from 6 to 16 mmHg.
  • Right atrial pressure increased slightly for the experimental group receiving SQ infusion of VD from Day 0 to Day 10.
  • the increase observed for the experimental group is significantly less than for the control group.
  • the data presented on FIG. 19 indicates a hemodynamic benefit for SQ infusion of VD for the HF model.
  • a decrease in the right atrial pressure is a protective cardiovascular effect.
  • FIG. 20 shows that pulmonary capillary wedge pressure increased as a result of HRP in both the control and experimental groups.
  • the extent of the increase in pulmonary capillary wedge pressure in the experimental group from Day 0 to Day 10 is smaller than that observed in the control group from Day 0 to Day 10.
  • the difference in pulmonary capillary wedge pressure between the control group and the experimental group on Day 10 does not appear to be statistically significant (alpha-0.05, two-way repeated measures ANOVA).
  • FIG. 21 shows the level of Pre-proANF (56-92) measured in plasma on Day 0 and Day 10 of the study. Plasma samples were analyzed using a radioimmunoassay to determine plasma concentrations. The data in FIG. 21 shows a significant increase in peptide of Pre-proANF (56-92) concentration between Day 0 and Day 10 in the VD-treated canines and a statistically significance between the buffer-infused control group canines and the VD-infused experimental group canines on Day 10. The difference in levels of Pre-proANF (56-92) observed reinforces the confidence that the pump continuously and successfully delivered VD over the 10-day infusion period.
  • Pre-proANF (56-92) plasma concentration was measured by radioimmunoassay in samples collected on Day 0 before vessel dilator infusion and after 10 days of continuous vessel dilator infusion.
  • Pre-proANF (56-92) plasma concentration changed from 0.66+/ ⁇ 0.37 ng/ml on Day 0 to 41.14+/ ⁇ 6.31 ng/ml on Day 10 in experimental group canines that were infused with vessel dilator.
  • Plasma levels in control animals that were infused with buffer were 0.60+/ ⁇ 0.17 ng/ml on Day 0 and 3.72+/ ⁇ 0.76 ng/ml on Day 10.
  • Cardiac output (CO) and mean arterial pressure (MAP) were also measured in both experimental and control canine groups.
  • CO and MAP decreased following 10 days of high-rate pacing, but there was no treatment effect from vessel dilator infusion.
  • Other outcomes that were measured were urinary potassium, protein, and creatinine excretion, serum renin, angiotensin, aldosterone, creatinine, urea, albumin, total protein, ANP, and NT-proBNP levels, cardiac function from echocardiogram, and gross and histologic pathology assessment. There were no significant treatment effects observed in these outcomes.
  • VD The pharmacodynamic effects of VD were investigated in a rat model. Forty male Dahl/SS rats were shipped to the animal facilities at PhysioGenix, Inc. (Milwaukee, Wis.). The rats were maintained on a low-salt diet and allowed to acclimate. After acclimation, animals had baseline parameters collected while on the low-salt diet. Baseline tail-cuff blood pressures and echocardiograms were measured. Baseline urine was collected for analysis of protein and albumin. Animals were then randomly assigned to one of 4 groups (10 animals per group):
  • Lyophilized VD peptide (Bachem) was reconstituted in a Tris buffer having the same composition as the Tris buffer used in Example 7.
  • the vehicle control groups were infused with a citrate-mannitol-saline buffer (0.66 mg/mL citric acid, 6.43 mg/mL sodium citrate, 40 mg/mL mannitol, 9 mg/mL NaCl).
  • the animals were on a Teklad 7034 (low-salt) diet or Dyets AIN-76A 4% salt diet, as indicated, throughout a 6 week course of the study and had free access to water.
  • Alzet® minipumps (Durect, Corp.) were surgically implanted on Days 1, 15, and 29 of the study to maintain continuous vehicle or drug dispensing at the desired dose for a total period of 6 weeks.
  • Urine was collected at baseline, 2, 4 and 6 weeks after the initiation of the treatment to assess proteinuria and albuminuria. After six weeks of treatment, the animals were then euthanized.
  • FIGS. 22 A and B present the average blood pressure for the 2 vehicle control groups on the low-salt diet and the 4% salt diet compared with either the group receiving 100 ng/kg/min of VD by SQ infusion (low-dose VD) or 300 ng/kg/min of VD (high-dose VD) by SQ infusion, respectively.
  • Groups receiving the low-dose or high-dose of VD were maintained on the 4% salt diet.
  • blood pressure increased in all groups.
  • both the low-dose VD and the high-dose VD groups exhibited attenuated blood pressure compared with the vehicle control group on the 4% salt diet.
  • the vehicle control group on the 4% salt diet showed a statistically significant increase in blood pressure compared with the control group on the low-salt diet (p-value ⁇ 0.05).
  • both the high-dose VD group and the low-dose VD group showed a statistically significant decrease in blood pressure compared with the 4% vehicle control group (p-value ⁇ 0.05).
  • the decrease in blood pressure of the high-dose VD group and the low-dose VD group at week 5 is not as statistically significant when compared with the 4% vehicle control group at week 5. Nonetheless, the groups treated with VD appear to exhibit protection against blood pressure increase induced by a high-salt diet.
  • the standard error for all groups is shown by error bars. Reduction in blood pressure is a renal or cardiovascular effect.
  • FIG. 23 presents the 24-hour albumin excretion in urine (mg/day) for the 2 vehicle control groups on low-salt and 4% salt diet, the group receiving the low-dose VD treatment and the high-dose VD treatment by SQ infusion.
  • albuminuria increased significantly in the vehicle control group on the 4% salt diet in weeks 2, 4 and 6 compared with the vehicle control group on the low salt diet (p-value ⁇ 0.05).
  • the high-dose VD group had dramatically lower levels of albumin excretion in the urine at weeks 2, 4 and 6 compared with the vehicle control group on the 4% salt diet (p-value ⁇ 0.05).
  • the effect on reducing albuminuria was not as pronounced in the low-dose VD group.
  • VD infusion appeared to have a positive impact in lowering albuminuria, which is a sign of improved renal function.
  • FIGS. 24A and B present the 24-hour protein excretion in urine (mg/day) for the 2 vehicle control groups on low salt diet and 4% salt diet with either the group receiving the low-dose VD treatment or the high-dose VD treatment by SQ infusion, respectively.
  • proteinuria increased significantly in the vehicle control group on the 4% salt diet in weeks 2, 4 and 6 compared with the vehicle control group on the low salt diet (p-value ⁇ 0.05).
  • the standard error for all groups is shown by error bars.
  • the high-dose VD group showed lower levels of protein excretion in urine at weeks 2, 4 and 6 compared with the vehicle control group on the 4% salt diet.
  • the reduction of proteinuria compared with vehicle control group on the 4% salt diet appears to be statistically significant (p-value ⁇ 0.05).
  • the effect on reducing proteinuria was not as pronounced in the low-dose VD group, as shown in FIG. 24A .
  • VD infusion appears to have a positive impact in lowering proteinuria, which is a sign of improved renal function and can be a renal protective effect.
  • the standard error for all groups is shown by error bars.
  • FIG. 25 presents renal cortical blood flow (as measured in perfusion units (PU)) for the 2 vehicle control groups on low-salt and 4% salt diet and with the groups receiving the low-dose VD treatment or the high-dose VD treatment by SQ infusion.
  • PU perfusion units
  • FIG. 25 renal cortical blood flow increased in the two groups receiving VD peptide relative to the vehicle control groups at week 6.
  • the group receiving the high-dose VD peptide showed significantly increased renal cortical blood flow relative to both the vehicle control group on the 4% salt diet and the low salt diet at the end of the study (p-value ⁇ 0.05).
  • the standard error for all groups is shown by error bars.
  • An increase in renal cortical blood flow is a renal protective effect.
  • FIG. 26 presents creatinine clearance data for the two vehicle control groups on low-salt and 4% salt diets and for the groups receiving the low-dose VD treatment and the high-dose VD treatment by SQ infusion.
  • Creatinine is a breakdown product produced in the muscle that is primarily filtered out of the blood by the kidneys and subsequently excreted in the urine. Creatinine clearance compares the level of creatinine in the urine with the level of creatinine in the blood, and provides an estimate of glomerular filtration rate.
  • the creatinine clearance data reported in FIG. 26 were calculated using the following formula: urine flow (mL) ⁇ urine creatinine concentration (mg/dL) ⁇ plasma creatinine concentration (mg/dL).
  • Creatinine clearance is influenced by the number of viable nephrons and the perfusion pressure applied to the nephrons. As shown in FIG. 26 , by week 2 of the study, creatinine clearance increased significantly compared to the baseline creatinine clearance. The increase affected the low-salt diet control group as well as the 4% salt diet control group. The results showing an increase in creatinine clearance for all groups can be explained by an increase in perfusion pressure in the nephrons brought about by increased blood pressure, as shown in FIG. 22 .
  • Histopathology was performed on the kidneys and hearts of all four groups after the conclusion of the 6-week study.
  • the histopathology data showed that the control group on the 4% salt diet had become fibrotic during the course of the study. In contrast, less renal damage was observed in both groups receiving VD by SQ infusion.
  • the histopathology results for kidney assessment are shown in Table 12 and for heart assessment in Table 13.
  • kidneys from all 3 groups on the 4% salt diet showed similar changes in histopathology with varying severity.
  • Kidneys were characterized by tubules in the cortex and medulla that were dilated, lined by flattened epithelial cells, and filled with eosinophilic homogenous proteinaceous material (casts). Areas of interstitial chronic inflammation were present scattered through mainly the cortex, with associated regions of tubular degeneration and regeneration, and interstitial fibrosis. Glomeruli were often hypercellular and enlarged with mesangial deposits and thickened capillary loops. Some were more shrunken and fibrotic with adhesions to the inner lining of Bowman's capsule. There was occasional peri-glomerular fibrosis.
  • FIG. 27 shows blood urea nitrogen (BUN) for the vehicle control groups on the low-salt and 4% salt diets as well as the two groups receiving the low-dose VD treatment and the high-dose VD treatment.
  • BUN was measured as serum urea in units of mg/dL.
  • BUN or serum urea concentration is a commonly monitored marker where elevation of BUN is indicative of renal injury or dysfunction by indicating a decreased ability to remove urea from the blood.
  • serum urea was significantly lower in both VD-treated groups compared to both control groups. Although this difference appeared to be statistically significant with a p-value less than 0.05, this difference may only represent individual animal variability in the model.
  • FIG. 28 shows urine cyclic GMP (cGMP) levels for the vehicle control groups on the low-salt and 4% salt diets as well as the two groups receiving the low-dose VD treatment and the high-dose VD treatment in units of mmol/day.
  • Cyclic GMP is a known second messenger generated in response to natriuretic peptides. Urine cGMP levels were measured to evaluate potential upregulation of this second messenger as a result of VD delivered by subcutaneous infusion.
  • urine cGMP was elevated at a constant level at weeks 2, 4, and 6 in the 4% salt diet control group and urine cGMP remained steady at a lower level throughout the duration of the study in the low-salt diet control group.
  • Cyclic GMP levels in the drug-treated groups stayed lower than the cGMP levels in the high-salt diet control group, which suggest that VD at either dose did not activate cGMP above levels stimulated by the high-salt diet itself.
  • FIG. 29 shows serum prostaglandin E 2 (PGE2) levels for the vehicle control groups on the low-salt and 4% salt diets as well as the two groups receiving the low-dose VD treatment and the high-dose VD treatment in units of pg/mL.
  • PGE2 levels were measured at week 6 of drug treatment.
  • VD caused a dose dependent increase in PGE2 serum levels, with the PGE level in the high-dose group having a statistically significant increase compared to both control groups. This finding is consistent with previous evidence of PGE2 involvement in the mechanism of action of VD, where PGE2 is known to relax smooth muscles. Other physiological parameters were measured during the 6-week course of the study and are briefly reported here.
  • Serum ANP levels were elevated in high-salt diet control animals at week 6 but not in vessel dilator treated animals.
  • Other outcomes that were measured in blood serum were renin, aldosterone, NT-proBNP, a panel of metabolic markers that included glucose, total protein, and electrolytes, and a panel of kidney injury markers that included cystatin-C, NGAL, and beta-2-microglobulin.
  • Urinary sodium and potassium excretion were also measured, and echocardiograms were performed to assess cardiac function. There were no remarkable treatment effects observed in these outcomes between experimental groups receiving VD and the control groups.
  • CHF chronic heart failure
  • a diuretic therapy usually a loop diuretic, such as furosemide, in combination with an Angiotensin-Converting Enzyme (ACE) Inhibitor, may be used to control symptoms of CHF.
  • ACE Angiotensin-Converting Enzyme
  • VD is also referred to in the literature as proANP [31-67] in reference to VD's origination from amino acids 31-67 of the ANP prohormone, where VD can be artificially synthesized.
  • VD is a 37 amino acid fragment of proANP and consists of a single linear chain amino peptide.
  • VD has been demonstrated to be well-tolerated in both canine and rat models.
  • average steady state peak concentrations were 257-287 ng/mL and 485-527 ng/mL, for the male canine and female canine, respectively.
  • Average peak steady state plasma concentrations in males were 17, 182 and 215 ng/mL, and in females 29, 281 and 475 ng/mL, for the three dose groups.
  • the study described herein is designed to evaluate the pharmacokinetic characteristics of VD peptide during steady state conditions during and following a 6-hour subcutaneous infusion of VD peptide. Further, the study is designed to evaluate the safety and tolerability of VD, to assess the non-invasive haemodynamic effects of VD, to evaluate whether VD has effects on renal function, and to quantify and to compare plasma concentrations for VD obtained by two different assays, a radioimmunoassay (RIA) and tandem mass spectrometry assay (LC/MS/MS).
  • RIA radioimmunoassay
  • LC/MS/MS tandem mass spectrometry assay
  • the study can be an open-label study without a placebo, where the identity of the administered drug is known by the attending clinicians.
  • the study can be of sequential group design with continuous, 6-hour, subcutaneous infusion utilizing an adaptive design and conducted at a single center with subjects having stable chronic heart failure and moderate renal impairment. Two steady state plasma concentrations (Css) of VD will be targeted at approximately 10 and 20 ng/mL.
  • the dosing will be sequential, starting with a lead-in of 2 patients at the lower targeted C ss of 10 ng/mL.
  • the 2 lead-in patients can be used to confirm that the measured plasma concentrations are in agreement with the targeted steady state plasma concentration.
  • the pharmacokinetic, safety and tolerability data from the two lead-in patients will be evaluated and, if warranted by the results, a revision of assessment timings and/or infusion rates and duration of dosing may be carried out prior to dosing a cohort of the further 8 patients at the same target concentration of 10 ng/mL.
  • the lower target C ss 10 ng/mL, is expected to be haemodynamically well-tolerated
  • the participants in this study will be selected to have stable cardiac disease, which is expected to increase tolerance to increased exposure to VD compared to less stable patients from a haemodynamic standpoint;
  • Any symptomatic hypotension is expected to be manageable by posture, fluid loading and close observation until the effects have attenuated due to clearance of VD from an affected patient.
  • Subjects that have had their infusion stopped will be required to stay under observation until the principal investigator (PI or Investigator) conducting the study or a designee is satisfied that the participant can be safely discharged home.
  • Assessments will include, but not be limited to, vital signs including BP and pulse and any other assessment deemed clinically relevant by the PI, including, e.g., IV fluid replacement every four hours during a 24 hour period.
  • FIG. 30 shows the proposed collection of assessments for the period prior to subcutaneous infusion and during the 6-hour subcutaneous infusion session. As shown in FIG. 30 , assessments will be taken at 21 days prior to the beginning of VD infusion and the day prior (Day 1 pre) to the beginning of VD infusion to establish appropriate baselines, as indicated by the placement of “x's.” Assessments will also be taken during the 6-hour infusion period as indicated by the placement of “x's” in FIG. 30 .
  • screening of patients with stable chronic heart failure will occur no more than 21 days prior to the beginning of subcutaneous infusion, although screening may occur at a later time.
  • Subjects with stable chronic heart failure will be recruited from outpatient cardiology sources including private cardiologists, as coordinated by the PI of the study. The study will enroll sufficient participants to allow for a total of 18 evaluable subjects, the two lead-in subjects and a cohort of eight subjects at each dose level as indicated in Scheme 1.
  • Urinalysis including urinary protein excretion
  • Noninvasive cardiac imaging with TTE 10.
  • Vital sign assessments including non invasive lying and standing BP, pulse, pulse oximetry, heart rate, respiratory rate and temperature;
  • Electrocardiogram ECG
  • Baseline renal function will be assessed in a period between the above-described screening and at least 2 days prior to the beginning of infusion on Day 1. Renal function will be assessed by measurement of the systematic clearance of 99Tc-MAG3 (technetium-99 mercaptoacetyltriglycine). 99Tc-MAG3 will be administered intravenously and blood samples will be taken at 5, 10 and 15 minutes, and 1, 2 and 3 hours after administration to assess clearance and baseline renal function.
  • 99Tc-MAG3 technetium-99 mercaptoacetyltriglycine
  • the main part of the study will comprise a single residential stay of approximately 28 hours including periods during the 6-hour infusion period and before and after the infusion.
  • Patient participants will arrive in the morning (e.g. at approximately 0800) on Day 1 (dosing day) after a light breakfast at home approximately two hours prior to the beginning of infusion dosing.
  • Caffeine and other xanthines such as cola or chocolate containing foodstuffs, grapefruit and alcohol consumption will not allowed for 24 hours prior to Day 1 and for the entire residential period.
  • An IV cannula will be placed into a forearm vein for blood sampling. This cannula will remain in situ and be re-sited as required.
  • the order of priority will be as follows: Adverse Event (AE) assessment, non-invasive cardiac output measurements and pharmacokinetic parameters.
  • AE Adverse Event
  • non-invasive cardiac output measurements and pharmacokinetic parameters.
  • six-hour sample after start of infusion for pharmacokinetics must be taken immediately before the end of infusion session.
  • Urine pregnancy test for WOCBP 2. Any participant with a calculated screening GFR of 25 ⁇ GFR ⁇ 35 ml/min will be required to have a pre-dose MBA20 (lipids and liver function) to calculate GFR prior to dosing. A GFR below 25 mL/min, or a clinically significant decline in GFR from the screening, as reviewed and assessed by the PI or designee, will preclude the participant from further participation in the study; 3. CK-MB (isozymes of phosphocreatine kinase) and Troponin-T; 4. Plasma proBNP and NT-proBNP levels; 5. Spot urine for Na+, K+ and creatinine; 6.
  • MBA20 lipids and liver function
  • kidney injury molecule-1 (KIM1), neutrophil gelatinase lipocalin (NGAL) and Cystatin-C; 7. Vital sign assessments (blood pressure (BP), heart rate (HR), pulse, pulse oximetry, temperature, respiratory rate); 8. Non-invasive cardiac imaging with TTE; 9. Non-invasive cardiac output monitoring with Cheetah NICOM®; 10. electrocardiogram (ECG); and 11. Blood sample for VD pharmacokinetic calculation prior to start of infusion.
  • Urine tests can be done at any time before start of infusion but NICOM, ECG and vitals will be performed before cannulation and within an hour of start of infusion.
  • Study drug administration can take place at approximately midday (e.g. noon) on Day 1, the dosing day. Participating subjects should be instructed to take their normal medications at home at approximately 6 am prior to arrival on the morning of Day 1 and should be instructed to bring in all regular medications for use during the study residential period. If dosing is begun at noon, the last assessment on Day 1 will be at midnight, 12-hour time point, which will give the participants 6 hours of undisturbed sleep. Regular medications will be administered at approximately 6 am on the morning of Day 2, at which time the participants may then return to sleep.
  • Pharmacokinetic samples for the quantification of VD plasma concentrations will be taken at 20, 40, 60, 80, 100 and 120 minutes, and at 2.5, 3, 3.5, 4, 4.5, 5, and 6 hours after start of infusion. The 6-hour sample must be taken immediately prior to end of the infusion; 2. Following the end of infusion, pharmacokinetic samples will be taken at 20, 40, 60, 80, 100 and 120 minutes, and at 2.5, 3, 3.5, 4, 4.5, 5, 6 and 24 hours after end of infusion; 3. Biochemistry (MBA20) and FBE (full blood analysis) will be obtained at 6 and 24 hours; 4. CK-MB and Troponin-T will be measured at 6 and 24 hours; 5. Plasma BNP and NT-proBNP will be measured at 6 and 24 hours; 6.
  • Continuous urine collection will be carried out throughout three collection intervals, 0-6, 6-12 and 12-24 hours. An aliquot of urine will be taken from the total urine volume at the end of each collection interval for the assessment of renal safety biomarkers (KIM1, NGAL and Cystatin-C), Na + , K + , creatinine and VSDL concentration; 7. Urine volume will be recorded continuously to observe for urine volume reduction; 8. Urine samples for urinalysis will be taken at 24 hours; 9. Vital sign assessments (NIBP (non-invasive blood pressure), HR, respiratory rate, temperature, pulse and pulse oximetry) will be carried out every 10 minutes during the first hour, 15 minutely to 4 hours, 30 minutely to 8 hours, hourly to 12 hours and at 24 hours; 10.
  • NIBP non-invasive blood pressure
  • HR respiratory rate
  • temperature temperature
  • pulse and pulse oximetry will be carried out every 10 minutes during the first hour, 15 minutely to 4 hours, 30 minutely to 8 hours, hourly to 12 hours and at 24 hours; 10.
  • Sampling for plasma concentrations of VD will be carried out during 24 hours following start of dosing, as described above. Samples will be taken as outlined in FIGS. 30 and 31 . Following the evaluation of the pharmacokinetic results from the 2 lead-in patients, the sampling schedule may be revised as indicated by the results from the lead-in patients. Sampling times may be changed and number of samples may be decreased.
  • Method 1 is an LC/MS/MS technique that extracts VD and an internal standard from human plasma using protein precipitation extraction.
  • the analytes can be separated by HPLC on a reverse phase C18 column and the species emerging from the HPLC column monitored by an API4000 MS/MS detector in MRM (multiple reaction monitoring) mode.
  • the data can then be assayed against a calibration curve and processed by the Analyst® data acquisition system linked directly to the API4000 MS/MS detector.
  • the method range for quantization can be from 0.2 ng/mL (LLOQ, lower-limit of quantitation) to 100 ng/mL.
  • VD RIA radioimmunoassay
  • the VD RIA is a competitive immunoassay in which a constant concentration of 125 I radiolabeled peptide (Phoenix Pharmaceuticals, Burlingame Calif., USA) and varying concentrations of unlabeled standard (VD-HCl, Auspep, Tullamarine Victoria, Australia) or sample peptide compete for binding specifically to the antiserum (Bachem, Torrance Calif., USA).
  • Immunocomplexes are precipitated by addition of an excess of non-specific serum and secondary polyclonal antiserum followed by centrifugation to separate bound and unbound peptide.
  • the method range for quantization for Method 2 can be from 0.9 ng/mL (LLOQ) to 49.1 (ULOQ, upper-limit of quantitation).
  • Noninvasive cardiac parameters including NIBP, heart rate, respiratory rate, pulse and pulse oximetry will be measured by a Philips IntellivueTM MP5 bedside monitor.
  • Noninvasive cardiac output monitoring will be carried out with the Cheetah NICOM® device at the bedside during 24 hours following start of VD infusion, as outlined in FIGS. 30 and 31 .
  • the Cheetah NICOM® device measures changes in the frequency of a low alternating current applied across the thorax to further changes in stroke volume, and hence combined with heart rate it estimates cardiac output.
  • the device is simple to use and consists of 4 pairs of electrodes applied at the base of the patient's neck and at the base of the thorax.
  • the device gives continuous real-time estimates of cardiac output. This non-invasive technique has been validated against traditional invasive methods such as thermodilution and has been approved by the FDA in the US and other appropriate authorities in other jurisdictions. The device will be used as per manufacturer's instructions. For further details see http://www.cheetah-medical.com/products/validation.
  • Transthoracic echocardiography using a Philips 1E33TM, will be used to measure estimated EF % (ejection fraction) (3D and 2D Simpson's), systolic and diastolic strain estimation (speckle tracking, E/E′ and tissue doppler) and estimates of PA (pulmonary artery) pressure (PA acceleration time, TR jet peak velocity).
  • EF % ejection fraction
  • systolic and diastolic strain estimation spekle tracking, E/E′ and tissue doppler
  • PA pulmonary artery pressure
  • MAG3 has a high renal clearance and is considered a marker of renal blood flow. This procedure was introduced in 1986 and is considered a standard choice in routine practice.
  • 99Tc-MAG3 will be administered as an IV 3 hours after start of VD infusion. Repeated measurements will be taken during 3 hours following administration of 99Tc-MAG3, as outlined FIG. 30 .
  • the time of administration can be chosen to correspond with an approximate steady state of VD and sampling of 99Tc-MAG3 may be completed prior to end of VD infusion.
  • a baseline measurement of 99Tc-MAG3 clearance will be carried out, as described in FIG.
  • the radiation dose, for each assessment with 99Tc-MAG3 is estimated to be 20 MBq (megabecquerel) and thus a cumulative dose of 40 MBq, i.e. in total 0.4 mSv (milli Sievert), for the two assessments.
  • Safety assessments will be assessed by spontaneous AE reporting, ECGs and blood analysis (FBE, biochemistry, CK-MB, plasma BNP and NT-proBNP, and Troponin-T), urinalysis and urine protein excretion assessment, noninvasive cardiac and vital sign parameters (including but not be limited to BP, HR, pulse oximetry, pulse, temperature, respiratory rate), urine volume and fluid input monitoring, physical examination, routine urinalysis and assessment of renal blood flow.
  • Renal safety biomarkers KIM, NGAL and Cystatin-C
  • Pharmacokinetics can be evaluated at two target concentration levels of VD, 10 ng/mL and 20 ng/mL, as described. Neither target is expected to be a significant safety concern and is expected to be high enough plasma concentrations to allow characterization of steady state pharmacokinetics and subsequent elimination following administration covering at least three half-lives of elimination of VD. Furthermore, continuous five day subcutaneous infusion of VD to rats and dogs showed no toxicity issues in concentrations up to approx. 740 and 500 ng/mL respectively and the maximum tolerated dose for prolonged subcutaneous administration is expected to be above 1300 and 2300 ng/kg ⁇ min for male and female rats, respectively, and 2000 ng/kg ⁇ min for canines.
  • the duration of infusion has been based on an anticipated 30 min (24-60 min) elimination half-life for VD in the plasma.
  • the subcutaneous absorption half-life may be difficult to estimate, but it is expected to be approximately 30 minutes based on the molecular weight of VD. Since it takes approximately five half lives to obtain a steady state concentration in the plasma, an infusion duration of six hours was chosen for this study to provide sufficient time to observe the steady state. The duration can be extended up to eight hours, as appropriate, following the evaluation of results from the lead-in participants in the present study described in Scheme 1.
  • the present study will initially dose only two patients, as a lead-in to the subsequent two cohorts as described in Scheme 1.
  • the VD infusion rate can be either decreased or increased to obtain the target C ss of 10 ng/mL in the first cohort of eight patients.
  • further study design details such as decrease in number of pharmacokinetic sampling times, actual timings of pharmacokinetic samples and other assessments can be revised in the attempt to optimize information gathering and minimize blood sampling, as informed by the results from the lead-in patients.
  • the maximum number of pharmacokinetic samples, or other assessments, will not likely change beyond what is presently defined.
  • the results from the first cohort will be evaluated and the infusion rate adjusted as appropriate to achieve the target C ss of 20 ng/mL in analogy with the results from the lead-in patients.
  • Patients in the present study will receive a fixed infusion rate, within a given target Css cohort, to allow the evaluation of the necessity for body weight adjusted dosing in future studies.
  • LVEF left ventricular ejection fraction
  • MI myocardial infarction
  • CK-MB creatine phosphokinase muscle-brain isoenzyme
  • SBP Severe valvular heart disease: aortic stenosis (AS), hypertrophic obstructive cardiomyopathy (HOCM), acute aortic incompetence (AI) or mitral regurgitation (MR); 8.
  • AS aortic stenosis
  • HOCM hypertrophic obstructive cardiomyopathy
  • AI acute aortic incompetence
  • MR mitral regurgitation
  • Diagnosis of syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH), Addison's disease or renal salt wasting disease; 16. Receipt of Investigational Drug within 30 days of screening or current enrolment in a clinical trial; 17. History of clinically significant drug or alcohol abuse within the past 12 months—as judged by the Investigator; 18. History of renal or cardiac transplantation; 19. Insufficient venous access; 20. History of current malignancy or malignancy requiring chemotherapy/radiotherapy within 2 years of enrolment (including any current or past history of prostatic malignancy); 21. History of nephrotic syndrome or clinically significant proteinuria (>1 g/24 hr); 22. Known history of infection with Hepatitis C, B or HIV; 23. Use of NSAIDS within 24 hours, or five half-lives, whichever is longer, of start of infusion; 24. History of chronic migraine (defined as >15 episodes per month); and 25. Inability to conform to the conditions of the protocol.
  • Patient participants will be advised that they are free to withdraw from the study at any time, for any reason, or if necessary, the Investigator may withdraw a participant to protect their health.
  • the Investigator may withdraw a participant if it is considered that the scientific and therefore ethical standards of the study are compromised. Participants may also be withdrawn for not complying with study procedures. The reasons for withdrawal will be fully documented. If a participant is withdrawn from the study due to an adverse event, treatment discontinuation must be explained on the adverse event form, as described below. The participant will be followed-up to the satisfaction of the Investigator.
  • VD Study drug
  • Auspep Clinical Peptides Tetramarine, Victoria, Australia
  • VD can be supplied as a white lyophilised powder composed of 1.0 mg of material containing an estimated 811 ⁇ g of peptide in 5 mL clear glass vials.
  • Elliotts B® Solution will be used to reconstitute the study drug for subcutaneous administration.
  • Directions B® Solution is a sterile, non-pyrogenic, isotonic buffer that is approved by the United States Food and Drug Administration (FDA) for intrathecal administration of methotrexate sodium and cytarabine.
  • FDA United States Food and Drug Administration
  • Directions B® Solution will be used as a diluent for VD since it provides the appropriate isotonicity and pH attributes desired for SC administration.
  • the stability and compatibility of VD in Elliotts B® Solution at relevant concentrations has been demonstrated.
  • the detailed contents of Elliots B® Solution are provided in the Trial Dispensing Protocol. Storage conditions of the raw material, Elliotts B® Solution, as well as the reconstitution method will be supplied in a Pharmacy Guideline provided during the study.
  • the system includes:
  • a programmable external drug pump (Model MMT722), 2. A drug reservoir, filled by trained staff in the RAH hospital pharmacy, that will hold the vessel dilator (Model MMT332A), 3. An infusion set (Model MMT396) that consists of tubing leading from the drug reservoir to a cannula that is inserted subcutaneously, and 4. A spring loaded inserter device (Model MMT395) is used to insert a small needle through the skin.
  • Additional information may be added to the label as required.
  • Investigational Product Only participants enrolled in the study will receive the Investigational Product (VD), in accordance with all applicable regulatory requirements. Only authorized site staff will receive, dispense or administer the Investigational Product (VD).
  • the Investigational Product (VD), including all components of the investigational devices, will be stored in a secure area with access limited to the Investigator and authorized staff and under physical conditions that are consistent with the Investigational Product specific requirements. The appropriate records of Investigational Product receipt, handling, usage and disposal for each participant will be maintained as per local practices and in accordance with regulatory requirements.
  • Study treatment must only be dispensed by a Pharmacist or medically qualified staff trained to fill, store and release study material. Once study treatment is prepared for a participant/patient, it can only be administered to that participant/patient. The Investigator will keep records of all doses of study drug dispensed to allow for reconciliation during and after the study according to all applicable laws and regulations. All components of the investigational devices used in the study will also be reconciled during and after the study.
  • participant ID number commencing at 001 or another similar number. This number will be allocated at the screening visit. Blinding will not be required as the study will have an open-label design. Drug compliance by participants/patients will be assured by the Investigator or designee supervising all study drug administration. There will be no interruption of a patient's usual therapy during the study. However, non-steroid anti-inflammatory drugs (NSAIDs) will not be not permitted for 24 hours or five half-lives, whichever is longer, prior to dosing on Day 1.
  • NSAIDs non-steroid anti-inflammatory drugs
  • VD can be administered via subcutaneous 6-hour infusion into the lower abdomen at a maximum volume rate of 350 ⁇ L/hr, i.e. approximately 6 ⁇ L/min.
  • the two infusion rates would be approximately 2.43 ⁇ g/min and 4.86 ⁇ g/min.
  • the final dosing rates will be higher to achieve the pre-defined target C ss levels, since bioavailability is expected to be lower than 100% for subcutaneous infusion.
  • intravenous fluids will be administered as appropriate. Any more unexpected, severe adverse events such as cardiogenic shock would be managed potentially with inotropic support or other cardiac support measures (i.e. balloon pump) as required in a specialized cardiac monitoring facility, although such events are not expected.
  • An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and does not necessarily have a causal relationship with the administration of VD.
  • An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
  • ADRs adverse drug reactions
  • An “Unexpected Adverse Reaction” is defined as the nature or severity of which is not consistent with previous observations during the administration of the drug product.
  • SAE Serious Adverse Event
  • Serious ADR Serious Adverse Drug Reaction
  • AE information will be and must be included (when applicable): the specific condition or event and direction of change; whether the condition was preexisting (i.e., an acute condition present at the start of the study or history of a chronic condition) and, if so, whether it has worsened (e.g., in severity and/or frequency); the dates and times of occurrence; severity; causal relationship to study drug or device; action taken; and outcome.
  • the causal relationship between an AE and the study drug will be determined by the Investigator based on his or her clinical judgment.
  • Mild (grade 1): The AE is noticeable to the subject but does not interfere with routine activity. The AE does not require discontinuing administration or reducing the dose of the study drug.
  • Moderate The AE interferes with routine activity but responds to symptomatic therapy or rest. The AE may require reducing the dose but not discontinuing administration of the study drug.
  • Severe (grade 3) The AE significantly limits the subject's ability to perform routine activities despite symptomatic therapy. In addition, the AE leads to discontinuing administration or reducing the dose of the study drug.
  • Life Threatening (grade 4): The AE requires discontinuing administration of the study drug. The subject is at immediate risk of death.
  • the Investigator will be obligated to assess the relationship between Investigational Product and the occurrence of each adverse event/serious adverse event.
  • the Investigator will use clinical judgment to determine the relationship.
  • Alternative causes such as natural history of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the Investigational Product will be considered and investigated.
  • the Investigator can also const an Investigator's Brochure that will be available during the study in the determination of his/her assessment.
  • the causal relationship of the adverse event to the Investigational Product (including the investigational device) or study procedures should be assessed by the Investigator (or medically qualified delegate).
  • Table 14 is a guide to Assessment of Relationship to study drug.
  • the adverse event follows a reasonable temporal sequence from the time of study product administration but could have been caused by the study subject's clinical state or other modes of therapy administered to the subject. Probable The adverse event follows a reasonable temporal sequence from the time of study product administration, abates upon discontinuation of the study product and cannot be reasonably explained by the known characteristics of the study subject's clinical state. Related The adverse event follows a reasonable temporal sequence from the time of study product administration, abates upon discontinuation of the study product and reappears when study product is reintroduced.
  • An SAE reporting form will be provided and available at the study site with detailed instructions regarding completion and contact information for reporting the SAE. Any SAE, regardless of causal relationship, will be reported to the sponsor immediately (no later than 24 hours after the investigator becomes aware of the SAE) by completing the SAE form and then confirming receipt by telephone that the form was received. Compliance with this time requirement is essential so that the sponsor may comply with its regulatory obligations.
  • Follow-up information relating to an SAE will be reported to the sponsor within 24 hours of receipt by the Investigator by sending a completed SAE form and confirming by telephone that the email was received.
  • the participant/patient should be observed and monitored carefully until the condition resolves or stabilizes or its cause is identified. Further, all SAE's will be reported to an ethics committee within 72 hours. If known, the diagnosis of the underlying illness or disorder should also be recorded, rather than its individual symptoms.
  • This study is designed to be an exploratory trial aimed at investigating the steady state pharmacokinetic characteristics of VD following subcutaneous infusion.
  • the number of participants is based on feasibility considerations aimed at providing information that will meet these objectives.
  • Data from subjects with missing or incomplete information may be included, but in such a manner as to minimize bias and not jeopardize quality of the output from the various analyses.
  • C max maximum observed peak concentration
  • t max time of Cmax
  • AUC area under the plasma concentration time curve
  • t 1/2 apparent volume of distribution
  • t 1/2 terminal half-life
  • C max,ss and t max,ss will be taken directly from the observed data.
  • AUC will be calculated using the linear up log down trapezoidal method to the last quantifiable concentration (C last ). The remainder will be extrapolated as C last /k where k z is the terminal rate constant determined by least-squares regression of the terminal slope of the log concentration-time curve.
  • CL/F will be calculated as Dose/AUC
  • Vz/F as CL/(F*k z )
  • t 1/2 will be calculated as ln 2/k z . Further analysis may be carried out as appropriate.
  • An exploratory analysis may also be carried out to obtain pertinent pharmacokinetic parameters and related variability.
  • the potential relationship between pharmacokinetic and pharmacodynamic variables e.g. selected haemodynamic or renal measures and/or adverse events will also be explored if warranted.
  • Potential pharmacokinetic/pharmacodynamic relationships will initially be explored by graphical presentation of data, followed by modeling of potential relationships, as appropriate.
  • the exploratory analysis may also utilize data from previous trials, as a pooled data set is expected to provide a better foundation for the determination of pharmacokinetic parameters, variability and pharmacokinetic/pharmacodynamic relationship(s).
  • Pharmacodynamic information will also be analyzed. Particularly, maximal change in pertinent non-invasively measured cardiac parameters. Variables of interest can be, but not limited to, cardiac index, left ventricular ejection fraction (LVEF) and arterial BP. The primary endpoints are changes in BP and cardiac output (CO).
  • cardiac index cardiac index
  • LVEF left ventricular ejection fraction
  • CO cardiac output
  • the study shall be performed in accordance with and to a timetable specified in study agreements between the Sponsor and involved parties, including but not limited to the clinical research site, data management service, and the bioanalytical facility (CPR Pharma Services Pty Ltd).
  • An independent monitor will be appointed to monitor the study in accordance with local regulatory guidelines and as per a Study Monitoring Plan to be provided. Safety monitoring will be by undertaken by the PI and optionally, a co-Investigator.
  • the study source documents and other supporting documentation will be the primary source of data for all assessments and measurements including vital signs, adverse events, timing of study procedures and concomitant medications.
  • the source document for the ECGs will be the paper readouts. Data will be recorded at specified time points for the Cheetah NICOM® device and comprehensive, continuous cardiac parameter information can be downloaded as required. Medical history obtained from the PI and recorded in the source book will be supported by any letters of referral or medical history obtained from previous investigations or outpatient/specialist reviews and from hospital in-patient notes where applicable and available.
  • Source documents will be original documents, data, and records from which the participants CRF data are obtained. These include, but are not limited to, hospital records, clinical and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence. CRF entries may be considered source data if the CRF is the site of the original recording (i.e., there is no other written or electronic record of data).
  • Quality of data transfer from source documents to CRFs shall be verified by on-site monitoring as per a Study Monitoring Plan to be provided.
  • Original CRFs shall be provided to data management who will enter the CRF data into the study database and reconcile it in a two-pass quality process.
  • a manual review of data and the discrepancy database shall be performed prior to the initiation of data rectification forms to the site staff and subsequent rectification of information in the database.
  • Medical coding shall precede duplicate quality control checks prior to database lock.
  • Clinical Trial Notification requirement of the appropriate regulatory authority will be met before commencement of the study.
  • the Sponsor will be responsible for reporting all serious, life threatening or fatal adverse events with a causal relationship to the Investigational Product to appropriate regulatory agencies within the required timelines.
  • Protocol amendments are alterations to a legal document and have the same legal status. Therefore, they must pass through appropriate steps before being implemented. In general, any important change that theoretically increases risk to subjects constitutes an amendment. Protocol modifications that impact on participants' safety or the validity of the study will be approved by the HREC. Minor changes such as administrative changes may be documented without approval, if permissible by the HREC.

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US11541205B2 (en) 2015-07-20 2023-01-03 Roivios Limited Coated urinary catheter or ureteral stent and method
US11612714B2 (en) 2015-07-20 2023-03-28 Roivios Limited Systems and methods for inducing negative pressure in a portion of a urinary tract of a patient
US11752300B2 (en) 2015-07-20 2023-09-12 Roivios Limited Catheter device and method for inducing negative pressure in a patient's bladder
US11896785B2 (en) 2015-07-20 2024-02-13 Roivios Limited Ureteral and bladder catheters and methods of inducing negative pressure to increase renal perfusion
US11904121B2 (en) 2015-07-20 2024-02-20 Roivios Limited Negative pressure therapy system
US11904113B2 (en) 2015-07-20 2024-02-20 Roivios Limited Ureteral and bladder catheters and methods of inducing negative pressure to increase renal perfusion
US11918754B2 (en) 2015-07-20 2024-03-05 Roivios Limited Ureteral and bladder catheters and methods of inducing negative pressure to increase renal perfusion
CN111315427A (zh) * 2017-05-24 2020-06-19 塞奎阿纳医疗有限公司 减少心力衰竭患者体内液体超负荷的直接钠移除方法、溶液和装置

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WO2012115772A3 (en) 2013-01-10

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