WO2015054246A1 - Procédés de traitement de sujets présentant une insuffisance rénale à l'aide de tédizolid - Google Patents

Procédés de traitement de sujets présentant une insuffisance rénale à l'aide de tédizolid Download PDF

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Publication number
WO2015054246A1
WO2015054246A1 PCT/US2014/059488 US2014059488W WO2015054246A1 WO 2015054246 A1 WO2015054246 A1 WO 2015054246A1 US 2014059488 W US2014059488 W US 2014059488W WO 2015054246 A1 WO2015054246 A1 WO 2015054246A1
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tedizolid
patient
subjects
renal
impairment
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PCT/US2014/059488
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English (en)
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Shawn Flanagan
Phillippe PROKOCIMER
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Trius Therapeutics, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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

Definitions

  • the present disclosure relates to the administration of tedizolid to subjects suffering from renal impairment for purposes of treating infections.
  • Tedizolid ((5i?)-3- ⁇ 3-fluoro-4-[6-(2-methyl-2H-te1razol-5-yl)pyridra-3- yl]phenyl ⁇ -5-(hydrox methyl)-l,3-oxazoiidin-2-one) is an oxazolidinone antibiotic.
  • Tedizolid phosphate the water-soluble prodmg of the active moiety tedizolid, is rapidly converted to tedizolid in the presence of endogenous phosphatases.
  • tedizolid The antibacterial activity of tedizolid is believed to result from its interaction with the 23S ribosomal ribonucleic acid (rRNA) of the bacterial ribosome to inhibit protein synthesis, thereby preventing the initiation of translation by inhibiting formation of the initiation complex.
  • Tedizolid shows potent in vitro activity against Gram-positive pathogens, including those resistant to other antimicrobial agents.
  • dose adjustments are required for many antibiotic classes in special patient populations, including patients with renal or hepatic insufficiency. Since renal and hepatic impairment are common comorbidities in patients requiring therapy for serious gram-positive infections, it is important to evaluate the potential need for dose adjustments with antibiotics used in this clinical setting. For example, chronic kidney disease is associated with increased overall and postsurgical infection risk and greater adverse outcomes, necessitating careful antibiotic use in these patients.
  • Chronic kidney disease With aging populations, the prevalence of chronic kidney disease (CKD) increases in both the community and hospitalized patients, with up to 50% CKD among nursing home residents. Dose adjustment calculations based on renal function are available, but achieving adequate target levels while avoiding adverse effects remains challenging.
  • CLD chronic liver disease
  • Chronic liver disease may be a risk factor for high vancomycin MIC methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections and MRSA infections caused by the SCCmec- IV strain, which is often community acquired.
  • MRSA methicillin-resistant Staphylococcus aureus
  • SCCmec- IV strain which is often community acquired.
  • CLD is associated with increased antibiotic adverse events. Serious liver disease can cause complex changes to drug metabolism and elimination through hepatic as well as renal pathways,
  • ESRD end-stage renal disease
  • a method for treating an infection in a subject with renal impairment comprising: identifying a subject with renal insufficiency; and administering a pharmaceutical composition comprising tedizolid to the subject.
  • the degree of the renal insufficiency of the subject may vary.
  • the subject may have severe renal impairment, or suffer from ESRD.
  • the subject is being treated with dialysis.
  • the pharmaceutical composition is administered intravenously.
  • the pharmaceutical composition comprising tedizolid can be administered to the subject in a single TV infusion of tedizolid 200 mg daily.
  • the pharmaceutical composition is administered orally.
  • the tedizolid is in the form of tedizolid hydrogen phosphate.
  • the infection is caused by gram-positive pathogens, for example, Staphylococcus aureus, Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius and Streptococcus constellatus), and Enterococcus faecal is (vaneomycin-susceptible isolates).
  • pathogens for example, Staphylococcus aureus, Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococc
  • the Staphylococcus aureus is methicillin-resistant (MRSA) or methicillin- susceptible (MSSA) Staphylococcus aureus.
  • the infection is an acute bacterial skin and skin structure infection (ABSSSI).
  • the Enterococcus faecalis is a vaneomycin-susceptible isolate.
  • the patient is being treated with hemodialysis.
  • the infection is hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP).
  • HABP hospital-acquired bacterial pneumonia
  • VABP ventilator-associated bacterial pneumonia
  • Figures 1 A-B show plasma tedizolid concentration in subjects with severe renal impairment and matched controls in linear scale (1A) and in semi-logarithmic scale (IB).
  • Figures 2A-B show plasma tedizolid concentration in subjects with impaired hepatic function and matched controls in linear scale (2A) and in semi-logarithmic scale (2B).
  • Figure 3 shows total plasma exposure, i.e. the area under the concentration-time curve (AUG), of tedizolid in evaluated special patient populations and relevant controls.
  • Figure 4 shows peak plasma concentration (C max ) in evaluated special patient populations and relevant controls.
  • the present disclosure relates to the treatment of an infection in a patient with organ impairment, for example, a patient with renal impairment, comprising administration of a pharmaceutical composition comprising a therapeutically effective amount of tedizolid.
  • a pharmaceutical composition comprising a therapeutically effective amount of tedizolid.
  • ESRD end-stage renal disease
  • tedizolid refers to (5 ?)-3- ⁇ 3-fluoro-4-[6-(2- methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl ⁇ -5-(hydroxymethyl)- 1 ,3-oxazolidin-2-one in a free-base or salt form, preferably a hydrogen phosphate form.
  • tedizolid is in its salt form, for example, a hydrogen phosphate form. This form has tht following formula:
  • tedizolid is in the form of disodium salt of tedizolid phosphate, and this form has the following structure:
  • Tedizolid is eliminated in excreta, primarily as a non-circulating and biologically inactive sulfate conjugate. Following single oral administration of C 34 ⁇ labeled tedizolid phosphate under fasted conditions, the majority of elimination occurred via the liver, with 81 .5% of the radioactive dose recovered in feces and 18.0% in urine, with most of the elimination (> 85%) occurring within 96 hours. Less than 3%) of tedizolid phosphate administered dose is excreted as active tedizolid.
  • tedizolid dosing and administration regimens for the treatment of an infection in a patient with renal impairment.
  • the patient with renal impairment include, but are not limited to, patients suffering from severe renal impairment without hemodialysis and patients experiencing end- stage renal disease (ESRD) undergoing hemodialysis.
  • ESRD end- stage renal disease
  • the pharmaceutical composition comprising tedizolid can be in various forms.
  • the pharmaceutical composition can be in the form of tablet.
  • each tablet of the pharmaceutical composition contains 200 mg of tedizolid phosphate, and inactive ingredients including, but not limited to, microcrystailine cellulose, mamiitol, povidone, crospovidone and magnesium stearate.
  • the pharmaceutical composition comprising tedizolid comprises a film coating that contains inactive ingredients including, but not limited to, polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, talc, and yellow iron oxide.
  • the pharmaceutical composition comprising tedizolid can also be an injectable form.
  • the pharmaceutical composition is an amount of white to off white sterile lyophilized powder for intravenous (IV) infusion which contains 210 nig of tedizolid phosphate to allow delivery of 200 mg after reconstitution with 4 rtiL of Sterile Water for injection.
  • the injectable form of the pharmaceutical composition comprising tedizolid can also contain inactive ingredients including, but not limited to, mannitol, sodium hydroxide, and hydrochloric acid, which is used in minimal quantities for pH adjustment.
  • the pharmaceutical composition comprising tedizolid is administered orally or intravenously.
  • a single 200 mg dose of tedizolid can be administered as an oral dosage form (such as an oral solution) or intravenously. Higher doses of tedizolid may also be used, such as about 300 mg or about 400 mg.
  • the pharmaceutical composition is orally administered at about 200 mg tedizolid once-a-day.
  • the pharmaceutical composition is intravenously administered as an infusion, such as a 60 ⁇ minute infusion.
  • the pharmaceutical composition comprising tedizolid is administered to the subject at about 200 mg once daily for six days either orally (with or without food) or as an intravenous (TV) infusion .
  • the pharmaceutical composition comprising tedizolid can also be administered to the subject for shorter or longer period of time, for example 2 days, 3 days, 4 days, 5 days, 7 days, 8 days, 9 days, 10 days, or longer.
  • compositions of tedizolid can be obtained by reacting the free acid dihydrogen phosphate with inorganic or organic bases such as sodium hydroxide or magnesium hydroxide.
  • pharmaceutically acceptable salts of the compounds disclosed herein e.g. , as made in situ during the manufacture of an intravenous formulation
  • Exemplary compositions for lyophilization and injection can be found in US Patent Publication No. 20100227839.
  • tedizolid phosphate can be formulated in situ as the disodrum salt using sodium hydroxide.
  • a compounding solution for lyophilization was prepared containing mannitol as a bulking agent, sodium hydroxide for in situ salt formation, hydrochloric acid for pH adjustment and water as a manufacturing solvent, which is removed during lyophilization.
  • a vial of the lyophilized composition may contain a 200 mg/viai dose of tedizolid phosphate.
  • the lyophilized material may be reconstituted, for example with 0.9% sodium chloride in water for injection. Renal Impairment
  • Non-limiting examples of bacterial infections that can be treated by the methods disclosed herein include infections caused by gram-positive bacteria, including but are not limited to. Staphylococcus, Streptococcus, Enterococcus, Clostridium, Haemophilus, Listeria, Corynehacterium, Bifidobacterium, Eubacterium, Lactobacillus, Leuconostoc, Pediococcus, Pepiostreptococcus, Propionibacterium, and Actinomyces ,
  • the methods disclosed herein can be used, for example, for the treatment of acute bacterial skin and skin structure infections (ABS8SI) caused by gram-positive bacteria including, but not limited to Staphylococcus bacteria (e.g., Staphylococcus aureus (including methiciilin- resistant (MRSA) and methici!lin-susceptible (MSSA) S.
  • ABS8SI acute bacterial skin and skin structure infections
  • Staphylococcus epidermidis Staphylococcus haemolyticus , Staphylococcus lugdunensis. Staphylococcus hominis, Staphylococcus saprophytics, and Staphylococcus epidermidis
  • Streptococcus bacteria e.g., Streptococcus avium, Streptococcus bovis, Streptococcus lactis, Streptococcus sangius, Streptococcus pneumoniae, Streptococcus agalactiae.
  • Streptococcus pyogenes and Streptococcus anginosus Group (e.g., Streptococcus anginosus. Streptococcus intermedins and Streptococcus consteUatus)), Enterococcus jaecalis (e.g., vancornycin-susceptible isolates), Enterococcus faecium, Clostridium bacteria (e.g., Clostridium difficile, Clostridium closlridioforme, Clostridium innocuura, Clostridium perfringens, and Clostridium ramosum), Listeria monocytogenes, Corynehacterium jeikeium, Eubacterium aerofaciens, Eubacterium lentum, Lactobacillus bacteria (e.g., Lactobacillus acidophilus, Lactobacillus casei, and Lactobacillus plantarum), Pepiostreptococcus bacteria (e
  • bacterial infection resulting from Staphylococcus aureus including niethiciliin-resistant S. aureus (MSSA and MRSA) isolates is treated or controlled using the methods disclosed herein.
  • MSSA and MRSA niethiciliin-resistant S. aureus
  • the MRSA isolate can be MRSA clone USA 300, or community-acquired methicilliii-resistant S. aureus (CA-MRSA).
  • the method is used to treat infection caused by one or more of Staphylococcus haemolyticus, Staphylococcus lugdunensis, coagulase-negative staphylococci, enterococcal (Enterococcus faecalis and Enterococcus faecium, including vancomycin-resistant enterococci (VRE)), and streptococcal species (Streptococcus pyogenes. Streptococcus agalactiae.
  • Staphylococcus haemolyticus Staphylococcus lugdunensis
  • coagulase-negative staphylococci enterococcal
  • enterococcal Enterococcus faecalis and Enterococcus faecium, including vancomycin-resistant enterococci (VRE)
  • streptococcal species Streptococcus pyogenes. Streptococcus
  • Streptococcus dysgalactiae including penicillin-susceptible Streptococcus pneumoniae (PSSP), penicillin-resistant S pneumoniae (PRSP), and multidrug-resistant (MDR) strains).
  • PSSP penicillin-susceptible Streptococcus pneumoniae
  • PRSP penicillin-resistant S pneumoniae
  • MDR multidrug-resistant strains
  • the method is used to treat an infection caused by one or more bacteria of the Streptococcus anginosus milled group (including Streptococcus anginosus, Streptococcus intermedins, and Streptococcus constellatus).
  • the method disclosed herein is used, in some embodiments, to treat an infection caused by a bacteria that is resistant to one or more ribosome-targeting antibiotics.
  • ribosome-targeting antibiotics include, but are not limited to, linezolid, clindamycin, streptogramins, phenicols, 16-membered macrolides, and pleuromutilins.
  • the method disclosed herein is used to treat an infection caused by vaneomycin-resistant and linezolid-resistant staphylococcal and enterococcai clinical isolates (including heteroresistant isolates) that possess the virulence factors Panton- Valentine leukoeidin toxin fPVL), pore-forming cytotoxins, and phenol- soluble modulins (PSM), cytotoxins that allow enhanced virulence, higher infectivity, and destruction of white blood cells (WBCs).
  • the method disclosed herein is used to treat acute bacterial skin and skin structure infection (ABSSSI) in adults and adolescents.
  • ABSSSI acute bacterial skin and skin structure infection
  • Non-limiting examples of clinical syndromes of ABSSSI include cellulitis, burns, major abscesses, infected ulcers, and wound infections.
  • the method disclosed herein is used to treat ventilated nosocomial pneumonia (VNP).
  • VNP ventilated nosocomial pneumonia
  • VNP include ventilator-associated bacterial pneumonia (VABP) and hospital-acquired bacterial pneumonia (HABP).
  • HABP is an acute infection of the pulmonary parenchyma, associated with clinical signs and symptoms such as fever or hypothermia, chills, rigors, cough, purulent sputum production, chest pain, or dyspnea, accompanied by a new or progressive infiltrate on a chest radiograph in a patient hospitalized for more than 48 hours or that develops within 7 days after hospital discharge.
  • VABP is associated with the same clinical syndrome as hospital-acquired bacterial pneumonia (HABP) with increased oxygen requirements in patients receiving mechanical ventilation via. an endotracheal tube for at least 48 hours.
  • the method disclosed herein can be used to treat M S A nosocomial pneumonia.
  • identifying the patient with renal insufficiency comprises evaluating the degree of renal insufficiency of the patient.
  • a number of methods are known to assess kidney function of a patient, including but are not limited to, blood urea nitrogen (BUN) test, ereatinine-blood test, creatinine clearance test, creatinine-urine test.
  • BUN blood urea nitrogen
  • ereatinine-blood test ereatinine-blood test
  • creatinine clearance test creatinine-urine test.
  • creatinine-urine test the amount of urea nitrogen in the blood is measured to assess kidney function and the normal results are generally from 6 to 20 mg/dL.
  • Creatinine is a breakdown product of creatine, which is an important part of muscle.
  • the amount of creatinine in the blood or urine can be determined to assess kidney function of a patient.
  • the normal results for the amount of creatinine in the blood are generally from 0.7 to 1.3 mg/dL for men and 0.6 to 1 .1 mg/dL for women.
  • the normal results for urine creatinine test are generally from 14 to 26 mg per kg of body mass per day for men and 1 1 to 20 mg per kg of body mass per day for women.
  • the normal results for creatinine clearance test are generally from. 97 to 137 ml min for men and from 88 to 128 ml/min for women.
  • a healthcare provider can evaluate the degree of renal insufficie cy of a patient using one or more methods known in the art.
  • a method for treating ventilator- associated bacterial pneumonia (VABP) and hospital-acquired bacterial pneumonia (HABP) in patient, with renal impairment comprising identifying a patient with renal insufficiency, and administering a pharmaceutical composition comprising tedizolid to the patient, wherein the patient also suffers from HABP or VABP.
  • VABP ventilator- associated bacterial pneumonia
  • HABP hospital-acquired bacterial pneumonia
  • kits format which comprises package units having doses and administration routes of tedizolid for treating an infection in a subject with rental insufficiency, for example a subject with severe rental insufficiency (eGFR ⁇ 30.0 rnL/rnin/1 .73m 2 ), or a subject with end-stage renal disease (eGFR ⁇ 15.0 mL/m.in/1 .73m 2 ),
  • a subject with severe rental insufficiency eGFR ⁇ 30.0 rnL/rnin/1 .73m 2
  • end-stage renal disease eGFR ⁇ 15.0 mL/m.in/1 .73m 2
  • the package label can include, for example, instructions to take tedizolid antibiotic for 6 days for the treatment of a bacterial infection in patients with renal insufficiency.
  • the package label can also include instructions for reconstitution and dilution in diluents/carrier for IV administration (e.g., water for injection, saline, Ringer's solution).
  • the package label includes instructions to treat a bacterial infection in patients with severe renal disease (eGFR ⁇ 30.0 mL/min/1.73m ) in which a dose of 200 mg tedizolid is administered daily for six days via an intravenous (IV) infusion.
  • severe renal disease eGFR ⁇ 30.0 mL/min/1.73m
  • IV intravenous
  • the package label includes instructions to treat a bacterial infection in patients suffering from end-stage renal disease (eGFR ⁇ 15.0 mL/min/1.73m 2 ) with hemodialysis in which a dose of 200 mg tedizolid is administered daily for six days via an intravenous (IV) infusion.
  • end-stage renal disease eGFR ⁇ 15.0 mL/min/1.73m 2
  • IV intravenous
  • the package label includes instructions to treat a bacterial infection in patients suffering from end stage renal disease (eGFR ⁇ 15.0 mL/min/1.73m 2 ) with hemodialysis in which a first dose of 200 mg tedizolid is administered via an intravenous (IV) infusion and a second dose of 200 mg tedizolid is administered via an IV infusion at least 7 days after the first dose of tedizolid is administered.
  • end stage renal disease eGFR ⁇ 15.0 mL/min/1.73m 2
  • IV intravenous
  • Packaged compositions are also provided that comprises a therapeutically effective amount of an antibiotic composition comprising tedizolid and a pharmaceutically acceptable carrier or diluents as well as instructions on how to treat a patient suffering from or susceptible to an infection, wherein the patient has renal insufficiency.
  • Tedizolid phosphate can be obtained using methods described in US patent publication No. 20100093669, which is incorporated herein by reference in its entirety and particularly for the purpose of describing tedizolid phosphate and methods for making it.
  • tedizolid is reconstituted in normal sterile saline (0.9% NaCl), to a. concentration of 200 mg/vial for tedizolid. Solutions can be stored at 25°C (77°F) until use.
  • tedizolid phosphate can be prepared as follows: A 5-L, jacketed round-bottom flask is equipped with an overhead, mechanical stirrer, addition funnel, thermocouple, nitrogen inlet, and a circulating chiller unit. The flask is charged with (R)-3-(4-(2-(2-methyltetrazoi-5-yl)pyridin-5-yl)-3-fluorophenyl)-5- hydroxymethyl oxazolidin-2-one (70.0 g, 0. 89 mol), THF (1.4 L, 20 vol), and triethylamine (58.2 g, 0.575 mol, 3 eq).
  • the slurry is stirred and the jacket temperature is set to 0°C.
  • the addition funnel is charged with phosphorus oxychloride (87.0 g, 0.567 mol, 3 eq) in THF (70 mL, 1 vol). Once the internal temperature reaches 1°C, the POCI 3 solution is added dropwise over 44 minutes. The maximum internal temperature is 2.2°C.
  • the mixture is stirred for 3 hours at 1 -2°C at which point HPLC analysis indicates that ⁇ 0.5% of the (R)-3-(4-(2-(2- methyltetrazoI-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one remains.
  • a 5-L, three-neck, round-bottom flask equipped with a Teflon diaphragm pump is charged with water (1.4 L, 20 vol) and is cooled to 3.8 °C. in an ice, salt water bath.
  • the reaction mixture is pumped into the quench water subsurface over 1 hour.
  • the maximum temperature during the quench is 1 1.9° C.
  • the reactor and pump lines are rinsed with water (-2 0 mL) into the quench vessel.
  • the yellow slurry is stirred overnight.
  • the slurry is filtered through Whatman paper, and the filter cake is rinsed with water (700 mL, 10 vol) and methanol (700 mL, 10 vol).
  • the product tedizolid phosphate is dried at room temperature in a vacuum oven until a constant weight is obtained.
  • compositions comprising one or more drug substances or excipients can be prepared in a variety of ways, including, for example, blending and lyophilization (also known as "co-lyophilization”).
  • lyophiiization is a process of freeze-drying in which water is sublimed from a frozen solution of one or more solutes. Specific methods of lyophilization are described in Remington's Pharmaceutical Sciences, Chapter 84, page 1565, Eighteenth Edition, A. R. Gennaro, (Mack Publishing Co., Easton, Pa., 1990).
  • Tedizolid is 4-16 folds more potent in vitro than linezolid against gram- positive pathogens, including methicillin-resistant Staphylococcus aureus and strains resistant to linezolid or vancomycin 1"3 and is rapidly bactericidal in vivo 4 .
  • tedizolid has demonstrated a favorable pharmacokinetic (PK) profile in healthy volunteers, including a. long half-life, minimal accumulation over time, high oral bioavailability (> 80%), and low inter-patient variability in drug exposure levels "' .
  • PK pharmacokinetic
  • Once daily dosing regimens of 200 mg, 300 nig, or 400 mg tedizolid phosphate resulted in similar efficacy outcomes in a Phase 2 study 1,6 .
  • Adolescents were compared to control results from multiple studies, since the study did not include a control population. These comparisons included calculation of PK parameter geometric mean ratios and associated 90% confidence intervals (Cis). A descriptive comparison of results was also obtained from special populations, controls from those studies as well as results from a multipart Phase 1 study of tedizolid phosphate conducted in healthy volunteers'".
  • the multi-part Phase I study comprised several subsequent stages: single ascending IV dose (Part A), multiple IV dose (Part B), and cross-over oral and IV bioavailability study (Part C).
  • Subjects were excluded if they were being treated with monoamine oxidase inhibitors or serotonergic agents within 14 days prior to the first tedizolid phosphate dose, or with direct or indirect sympathomimetic agents within 48 hours prior to the first tedizolid phosphate dose. Lifestyle restrictions included avoidance of high-tyramine diets, alcohol, and strenuous exercise 48 hours prior to tedizolid phosphate administration through to the follow up visit.
  • Additional exclusion criteria for the hepatic impairment study included alanine transaminase (ALT) > 5x the upper limit of normal (ULN) for moderate and > 8x ULN for severe disease, hemoglobin concentration ⁇ 10 rng/dL for moderate and ⁇ 9 mg/dL for severe disease, and total bilirubin > 5 for moderate disease (there was no limit for severe disease).
  • ALT alanine transaminase
  • UPN upper limit of normal
  • 8x ULN normal
  • hemoglobin concentration ⁇ 10 rng/dL for moderate and ⁇ 9 mg/dL for severe disease
  • total bilirubin > 5 for moderate disease (there was no limit for severe disease).
  • Evidence of acute deterioration of hepatic function within 8 weeks prior to screening, creatinine clearance ⁇ 50 mL/min, and ECG abnormalities (including QTc interval > 500 ms) were additional exclusion criteria.
  • individuals in both the control group and the nondialyzed severe renal impairment group received a single 60-minute infusion of 200 mg tedizolid phosphate.
  • Those in the ESRD group received 2 separate 60-minute infusions of 200 mg tedizolid phosphate in a non-randomized crossover design, with half of all subjects first receiving an infusion starting 1 to 1.5 hours prior to hemodialysis (using high flux hemodialysis and non-reuse filters) and the other half initially receiving an infusion starting within I hour of completion of hemodialysis. All subjects subsequently underwent the reverse sequence to the one to which they were initially assigned, with a minimum 7-day washout period required between infusions.
  • Controls and subjects with hepatic impairment were matched to compare the PK properties of a single dose of 200 mg tedizolid phosphate administered orally.
  • Cohort assignments (8 subjects in each group) were as follows: moderate hepatic impairment (Child- Pugh classification B; score of 7-9); severe hepatic impairment (Child-Pugh classification C; score of 10-15); and 16 controls (8 subjects matched to the moderate hepatic control group, 8 matched to the severe hepatic impairment control group) with normal hepatic function.
  • Control subjects were matched for age, sex, and BMi to each of the hepatic impairment groups. Group enrollment was sequential; the moderate hepatic impairment group was enrolled before the severe impairment group. Study drug was administered to subjects in a fasted (for at least 8 hours) state.
  • Serial plasma samples were collected from predose through 72 hours postdose for the renal impairment study and predose through 96 hours postdose for the hepatic impairment study.
  • Afferent and efferent plasma samples and clialysate samples (ESRD group only) were collected prehemodialysis and every 30 minutes during hemodialysis.
  • Samples were extracted with acetonitrile and precipitated with hydrochloric acid, followed by low-speed (3,800 x g) centrifugation at room temperature for 5 minutes. Supematants were evaporated to dryness and reconstituted in methanol/ ater (3:7, v/ ' v).
  • Tedizolid and tedizolid phosphate were separated by high-power liquid chromatography ( 1200 series; Agilent Technologies, Santa Clara, CA) with a Hypersil GOLD aQ column (50 x 3 mm, 5 -micron particle size) (Thermo Fisher Scientific, Waltham, MA). Samples were eluted using a gradient from 80% 20 mM ammonium phosphate (pH 9.0)/20% methanol to 80% methanol over 4.5 minutes at a flow rate of 0.5 mL/min. The column eluent was directed to an API 4000 triple quadrupole mass spectrometer (AB SCTEX, Framingham, MA) for compound quantification. Data were processed using the Analyst 1 .4.1 software package (AB SCIEX) and the Watson LIMS laboratory information management system (Thermo Fisher Scientific).
  • Standard noncompartmental analysis was conducted using WinNonlin Professional edition (Version 5.2; Pharsight Corporation, St. Louis, MO), and the following PK parameters were calculated for tedizoiid and tedizoiid phosphate when applicable: peak concentration in plasma Cmax ( , ug ⁇ 'niL), time at peak plasma concentration T max (hr), area under the concentration-time curve AUCo-t ⁇ g-hr/mL), AUCo- ⁇ ⁇ g-hr/mL), and apparent terminal half-life t ⁇ / 2 (hr).
  • the geometric mean ratios for tedizoiid C max , AUQ , and AUCo- ⁇ and corresponding 90% confidence intervals (CI) were determined for each study group and their corresponding controls using analysis of variance models.
  • the log- transformed PK parameter was the response variable
  • group was the fixed factor
  • subject was the random effect.
  • Plasma concentration-time profiles were generated for individuals receiving tedizoiid phosphate, and median or mean plasma concentration-time profiles (linear and semilogarithmic scales) were generated for each treatment group.
  • Linezolid PK is not consistently altered by renal insufficiency
  • a recent study confirmed that patients with hematologic abnormalities on linezolid therapy have lower estimated glomerular filtration rates and almost 2-fold higher linezolid C m . n levels.
  • Linezolid-associated thrombocytopenia rates are higher in patients with severe renal impairment and may be related to drug or metabolite accumulation, since renal insufficiency is also associated with significant increases in linezolid plasma metabolite levels.
  • Additional dosing considerations come into play when hemodialysis support is required, due to the faster clearance of small -molecular- weight compounds during dialysis.
  • tedizolid In contrast to the low (-30%) protein binding of linezolid, tedizolid demonstrates greater protein binding, even in patients with severe renal impairment. Because dialysis clearance is associated with the free drug fraction, it, is no surprise that the tedizolid clearance during hemodialysis (i.e., ⁇ 10% of the administered dose) is less than the -30% clearance for linezolid during dialysis. It is suggested that linezolid doses only be given after dialysis. Use of tedizolid phosphate, on the other hand, may allow for more flexible timing of dose administration in hemodialysis patients.
  • Each participant with severe renal impairment without dialysis received a single 60-minute IV infusion of tedizolid phosphate 200 mg.
  • Each participant with severe renal impairment with chronic hemodialysis received two 60-minute IV infusions of tedizolid phosphate 200 mg separated by a minimum of 7 days and examined for tedizolid pharmacokinetics before and after dialysis in a cross-over fashion.
  • Each participant, with normal renal function received a singl e 60-minute IV infusion of tedizol id phosphate 200 mg.
  • Table 2 Renal impairment study: baseline demographies
  • ⁇ SD ⁇ SD + ⁇ SD
  • the estimated calculation of GFR using the MDRD-4 calculation can overestimate glomerular filtration rate as a result of fluctuating plasma creatinine levels during and between dialysis sessions.
  • C max maximum concentration observed with 200 mg dose
  • T raax time to reach maximum concentration
  • AUCo-t integrated area under the curve based on samples from time 0 to the last collected sample
  • AUCo- the area under the curve based on terminal rate constant
  • t 1 ⁇ 2 tedizolid half-life.
  • tedizolid PK parameters were comparable between controls and subjects with severe renal impairment, including those with ES D. Since uremia is known to alter several aspects of non-renal drag clearance (including membrane transport functions) and because anomalous adverse event profiles have been noted when orally administered linezolid was studied in renal insufficiency, the administration of IV tedizolid phosphate in the present study allowed for a more sensitive assessment of tedizolid metabolism and excretion under ESRD conditions.
  • Tedizolid phosphate was generally well tolerated in subjects with severe renal impairment. Less than half of all treated subjects experienced at least one treatment- emergent adverse event, (TEAE); this included 3 subjects in the control group, 5 in the non- dialysis group, and 3 in the dialysis group. The only adverse event experienced by more than one subject per group was headache. Most of the TEAEs were mild or moderate in severity; 2 severe TEAEs (nausea and vomiting) were reported for one subject with severe renal impairment. No serious adverse events were reported,
  • the liver is an important site for dmg biotransformation (through phase 1 oxidative processes and/or phase 2 conjugation reactions) that can also influence PK through altered plasma protein binding or biliary excretion.
  • phase 1 metabolism tends to be adversely affected earlier in the course of disease, while phase 2 metabolism is more likely to be affected in severe liver disease.
  • Preclinical studies demonstrate that tedizolid is primarily metabolized through phase 2 conjugation reactions, in marked contrast to the oxidative metabolism of linezolid, which appears to be mediated through a phase 5 , non-cytochrome P450 mechanism.
  • the present study included subjects with moderate and severe hepatic impairment to fully understand the PK impact of a molecule with extensive hepatic metabolic and excretory features.
  • AUG or C max were not appreciably altered in subjects with moderate or severe hepatic dysfunction, compared to their respective control groups.
  • chronic liver disease and/or impaired liver function are risk factors for linezolid-associated thrombocytopenia and for isolated cases of delayed, but rapid-onset, lactic acidosis in adults and children.
  • Linezolid PK changes have not been formally evaluated in subjects with severe hepatic impairment, but an increase in linezolid AUC of ⁇ 1.3-fold was observed in subjects with mild to moderate hepatic impairment. This effect size is similar to the increase seen with tedizoiicl in subjects with even greater (i.e., severe) hepatic impairment, suggesting that larger increases in linezolid AUC may be expected in subjects with severe hepatic impairment.
  • Demographic data are presented as the mean + SD or as the number and percentage of the study population.
  • Cmax maximum concentration observed with 200 mg dose
  • AUCo-t integrated area under the curve based on samples from time 0 to the last collected sample
  • AUC0- ⁇ the are under the curve based on terminal rate constant
  • t 1 ⁇ 2 tedizolid half-life.
  • a 2-pa.rt, open-label study characterized the PK of tedizolid in adolescent subjects was conducted.

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Abstract

La présente invention concerne l'administration de tédizolid à des populations spéciales de patients, par exemple des sujets souffrant d'une insuffisance rénale, pour traiter des infections.
PCT/US2014/059488 2013-10-07 2014-10-07 Procédés de traitement de sujets présentant une insuffisance rénale à l'aide de tédizolid WO2015054246A1 (fr)

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CN105287407A (zh) * 2015-11-24 2016-02-03 南京正大天晴制药有限公司 一种注射用磷酸特地唑胺
CN106279282A (zh) * 2015-05-21 2017-01-04 博瑞生物医药（苏州）股份有限公司 一种磷酸特地唑胺的纯化方法
CN106317114A (zh) * 2015-07-02 2017-01-11 南京优科制药有限公司 一种磷酸特地唑胺的制备方法
CN107226825A (zh) * 2017-06-14 2017-10-03 浙江海正药业股份有限公司 磷酸泰地唑胺铵盐及其晶型、制备方法和医药用途
CN107353304A (zh) * 2017-07-12 2017-11-17 浙江普洛得邦制药有限公司 磷酸泰地唑胺三羟甲基氨基甲烷盐及其晶型a、制备方法和应用
CN110878349A (zh) * 2019-12-06 2020-03-13 深圳谱元科技有限公司 终末期肾病生物标志物及其应用

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106279282A (zh) * 2015-05-21 2017-01-04 博瑞生物医药（苏州）股份有限公司 一种磷酸特地唑胺的纯化方法
CN106317114A (zh) * 2015-07-02 2017-01-11 南京优科制药有限公司 一种磷酸特地唑胺的制备方法
CN105287407A (zh) * 2015-11-24 2016-02-03 南京正大天晴制药有限公司 一种注射用磷酸特地唑胺
CN107226825A (zh) * 2017-06-14 2017-10-03 浙江海正药业股份有限公司 磷酸泰地唑胺铵盐及其晶型、制备方法和医药用途
CN107226825B (zh) * 2017-06-14 2019-08-02 浙江海正药业股份有限公司 磷酸泰地唑胺铵盐及其晶型、制备方法和医药用途
CN107353304A (zh) * 2017-07-12 2017-11-17 浙江普洛得邦制药有限公司 磷酸泰地唑胺三羟甲基氨基甲烷盐及其晶型a、制备方法和应用
CN110878349A (zh) * 2019-12-06 2020-03-13 深圳谱元科技有限公司 终末期肾病生物标志物及其应用

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