EP3233063A2 - Régimes posologiques en trois phases pour l'administration d'antibiotiques en fonction du temps et dispositifs associés - Google Patents

Régimes posologiques en trois phases pour l'administration d'antibiotiques en fonction du temps et dispositifs associés

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Publication number
EP3233063A2
EP3233063A2 EP15870990.7A EP15870990A EP3233063A2 EP 3233063 A2 EP3233063 A2 EP 3233063A2 EP 15870990 A EP15870990 A EP 15870990A EP 3233063 A2 EP3233063 A2 EP 3233063A2
Authority
EP
European Patent Office
Prior art keywords
time
administering
dependent antibiotic
patient
antibiotic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP15870990.7A
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German (de)
English (en)
Other versions
EP3233063A4 (fr
Inventor
Pieter Muntendam
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SCpharmaceuticals Inc
Original Assignee
SCpharmaceuticals Inc
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Filing date
Publication date
Application filed by SCpharmaceuticals Inc filed Critical SCpharmaceuticals Inc
Publication of EP3233063A2 publication Critical patent/EP3233063A2/fr
Publication of EP3233063A4 publication Critical patent/EP3233063A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0097—Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present teachings relate to the administration of antibiotics. More specifically, the present teachings relate to biphasic and triphasic dosing regimens for administration of time-dependent antibiotics and devices for administering the same.
  • MIC minimum inhibitory concentration
  • a time-dependent antibiotic is above the MIC of an organism to be treated without requiring inpatient treatment and/or multiple infusions or administrations per day.
  • Such a therapy has the potential benefits of maximizing the effectiveness of the antibiotic treatment, reducing the cost of drug administration, and increasing the likelihood of patient compliance.
  • the present teachings provide methods for the treatment of infections and other diseases or conditions with dosing regimens of a time-dependent antibiotic that can address various deficiencies and short comings of the state-of-the-art including those mentioned above.
  • the dosing regimens can be biphasic or triphasic in administration of the time-dependent antibiotic.
  • the dosing regimens can occur over about 6 to about 12 hours and can be administered by a micropump or a patch pump device, which can permit controlled subcutaneous infusion of the time-dependent antibiotic with ambulatory or at-home treatment.
  • the triphasic dosing regimens of the present teachings generally include a loading phase (a first dosing period), a maintenance or continuous phase (a second dosing period), and a pre-removal or end bolus phase (a third dosing period).
  • the triphasic dosing regimen can be administered over about 6 hours to about 16 hours.
  • the loading phase can deliver a sufficient dose of the time- dependent antibiotic over about 15 minutes to about an hour, to achieve a plasma serum level of the time-dependent antibiotic above a minimum inhibitory concentration ("MIC") for an organism to be treated.
  • MIC minimum inhibitory concentration
  • the maintenance or continuous phase typically is the longest in time and can deliver a steady or continuous amount of the time-dependent antibiotic to maintain a plasma serum level of the time-dependent antibiotic above the MIC, for example, for at least a majority of this time period.
  • the maintenance or continuous phase can be from about 5 hours to about 14 hours.
  • the pre-removal or end bolus phase can deliver at least about 25% and up to about 70% of the daily dose of the time- dependent antibiotic over about 15 minutes to about an hour.
  • the triphasic dosing regimen can improve and/or maximize the time a patient's plasma concentration or level of the time-dependent antibiotic is above the MIC.
  • the triphasic dosing regimen of the present teachings can be administered subcutaneously, for example, using a micropump device or a pump patch device.
  • a patient can wear the device for about 6 hours to receive an effective daily dose of the time-dependent antibiotic and have 18 hours device-free without being attached to a constant intravenous ("IV") drip or receiving IV infusions every 6 to 8 hours.
  • IV intravenous
  • Being device-free also reduces interference with a patient's daily activities such as bathing and sleeping. Consequently, for at least these reasons, patient compliance should certainly improve with such a treatment regimen.
  • the present teachings provide methods of administering a time-dependent antibiotic to a patient.
  • the methods generally include the steps of: (a) administering to a patient between about 15% to about 35% of a daily dose of a time-dependent during a first dosing period, where the first dosing period is between about 3% to about 17% of a total time of administration; (b) administering to the patient between about 15% to about 40% of the daily dose of the time-dependent antibiotic for a second dosing period, where the second dosing period is between about 66% to about 94% of the total time of administration; and (c) administering to the patient between about 25% to about 70% of the daily dose of the time-dependent antibiotic for a third dosing period, where the third dosing period is between about 3% to about 17% of the total time of administration.
  • the methods generally include (a) administering to a patient a first dose of a time-dependent antibiotic sufficient to provide a plasma concentration of the antibiotic above a minimum inhibitory concentration, where administering the first dose occurs over a first dosing period of about 3% to about 17% of a total time of administration; (b) administering to the patient a second dose of the antibiotic sufficient to maintain the plasma concentration of the time- dependent antibiotic above the minimum inhibitory concentration for at least 50% of a second dosing period, where administering the second dose occurs over the second dosing period of about 66% to about 94% of the total time of administration; and (c) administering to the patient a third dose of the time-dependent antibiotic sufficient to maximize a plasma concentration of the time-dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic in step (a) and in step (b), where administering the third dose occurs over a third dosing period of about 3% to about 17% of the total time of administration.
  • the sum of the first, second, and third doses can equal a daily dose of the time-dependent antibiotic.
  • the methods generally include the steps of: (a) administering to a patient between about 15% to about 35% of a daily dose of a time-dependent antibiotic for a first dosing period, where the first dosing period is between about 15 minutes to about 60 minutes; (b) administering to the patient between about 15% to about 40% of the daily dose of the time-dependent antibiotic for a second dosing period, where the second dosing period is between about 4 hours to about 15.5 hours; and (c) administering to the patient between about 25% to about 70% of the daily dose of the time-dependent antibiotic for a third dosing period, where the third dosing period is between about 15 minutes to about 60 minutes.
  • the methods generally include the steps of: (a) administering to a patient a first dose of time-dependent antibiotic sufficient to provide a plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration, where administering the first dose occurs over a first dosing period of about 15 minutes to about 60 minutes; (b) administering to the patient a second dose of the time-dependent antibiotic sufficient to maintain a plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at least 50% of a second dosing period, where administering the second dose occurs over the second dosing period of about 4 hours to about 15.5 hours; and (c) administering to the patient a third dose of the time-dependent antibiotic sufficient to maximize a plasma concentration of the time-dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic in step (a) and in step (b), where administering the third dose occurs over a third dosing period of about 15 minutes to about 60 minutes.
  • the sum of the first, second and third doses can equal a daily dose of the time-dependent antibiotic.
  • the methods generally include a time-dependent antibiotic for use in a method for the treatment of an infection or other disease and condition that responds to time-dependent antibiotic treatment or therapy characterized in that the time-dependent antibiotic is administered as follows: (a) administering to a patient about 15% to about 35% of a daily dose of a time- dependent antibiotic during a first dosing period, wherein the first dosing period is about 3% to about 17% of a total time of administration; (b) administering to the patient about 15% to about 40% of the daily dose of the time-dependent antibiotic for a second dosing period, wherein the second dosing period is about 66% to about 94% of the total time of administration; and (c) administering to the patient about 25% to about 70% of the daily dose of the time-dependent antibiotic for a third dosing period, wherein the third dosing period is about 3% to about 17% of the total time of administration.
  • the methods generally include a time-dependent antibiotic for use in a method for the treatment of an infection or other disease and condition that responds to time-dependent antibiotic treatment or therapy characterized in that the time-dependent antibiotic is administered as follows: (a) administering to a patient a first dose of a time-dependent antibiotic sufficient to provide a plasma concentration of the antibiotic above a minimum inhibitory concentration, wherein administering the first dose occurs over a first dosing period of about 3% to about 17% of a total time of administration; (b) administering to the patient a second dose of the time-dependent antibiotic sufficient to maintain the plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at least 50% of a second dosing period, wherein administering the second dose occurs over the second dosing period of about 66% to about 94% of the total time of administration; and (c) administering to the patient a third dose of the time-dependent antibiotic sufficient to maximize a plasma concentration of the time- dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic in step (a
  • the methods generally include a time-dependent antibiotic for use in a method for the treatment of an infection or other disease and condition that responds to time-dependent antibiotic treatment or therapy characterized in that the time-dependent antibiotic is administered as follows: (a) administering to a patient about 15% to about 35% of a daily dose of a time- dependent antibiotic for a first dosing period, wherein the first dosing period is about 15 minutes to about 60 minutes; (b) administering to the patient about 15% to about 40% of the daily dose of the time-dependent antibiotic for a second dosing period, wherein the second dosing period is about 4 hours to about 15.5 hours; and (c) administering to the patient about 25% to about 70% of the daily dose of the time- dependent antibiotic for a third dosing period, wherein the third dosing period is about 15 minutes to about 60 minutes.
  • the methods generally include a time-dependent antibiotic for use in a method for the treatment of an infection or other disease and condition that responds to time-dependent antibiotic treatment or therapy characterized in that the time-dependent antibiotic is administered as follows: (a) administering to a patient a first dose of a time-dependent antibiotic sufficient to provide a plasma concentration of the antibiotic above a minimum inhibitory concentration, wherein administering the first dose occurs over a first dosing period of about 15 minutes to about 60 minutes; (b) administering to the patient a second dose of the time-dependent antibiotic sufficient to maintain the plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at least 50% of a second dosing period, wherein administering the second dose occurs over the second dosing period of about 4 hours to about 15.5 hours; and (c) administering to the patient a third dose of the time-dependent antibiotic sufficient to maximize a plasma concentration of the time-dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic in step (a) and in step (b), wherein administering the
  • the methods can include a two phase or biphasic dosing regimen.
  • Such methods generally can include the steps of: (a) administering to a patient about 25% to about 75% of a daily dose of a time-dependent antibiotic during a first dosing period, where the first dosing period is about 83% to about 96% of a total time of administration; and (b) administering to the patient about 25% to about 75% of the daily dose of the time-dependent antibiotic for a second dosing period, where the second dosing period is about 4% to about 17% of the total time of administration.
  • the present teachings also include a micropump device or a patch pump device for practicing the methods of the present teachings.
  • the micropump or patch pump device can include a reservoir containing an antibiotic composition, where the antibiotic composition includes at least one time-dependent antibiotic and a pharmaceutically acceptable carrier.
  • the micropump or patch pump device can include a subcutaneous injection needle configured for removable insertion into the skin of a patient; and a micropump having an inlet in fluid communication with the reservoir and an outlet in fluid communication with the subcutaneous injection needle.
  • the micropump or patch pump device can include a control system configured to control the micropump to deliver the antibiotic composition from the reservoir through the subcutaneous injection needle to a patient.
  • the micropump or patch pump can include a housing for supporting the reservoir, the subcutaneous injection needle, the micropump, and the control system. The control system can be configured to deliver the antibiotic composition in accordance with the methods (dosing regimens) of the present teachings.
  • FIGS. 1A-1C are histograms of MIC values for three test organisms: S. aureaus, P. aeruginosa and B.fragilis, respectively.
  • FIG. 2 is a schematic of the ceftriaxone pharmacokinetic model.
  • FIGS. 3-12 are the results of the pharmacokinetic simulations for each of the 10 dosing regimens analyzed including embodiments of biphasic and triphasic dosing regimens of the present teachings.
  • FIG. 13 is a graph depicting the results in Table 4 for S. aureaus for each of the 10 dosing regimens (x-axis), where the y-axis represents the median time in hours that simulated patients have a plasma concentration of ceftriaxone above the MIC for S. aureaus during the 72 hour treatment period.
  • FIG. 14 is a graph depicting the results in Table 4 for P. aeruginosa for each of the 10 dosing regimens (x-axis), where the y-axis represents the median time in hours that simulated patients have a plasma concentration of ceftriaxone above the MIC for P. aeruginosa during the 72 hour treatment period.
  • FIG. 15 is a graph depicting the results in Table 4 for B.fragilis for each of the 10 dosing regimens (x-axis), where the y-axis represents the median time in hours that simulated patients have a plasma concentration of ceftriaxone above the MIC for B. fragilis during the 72 hour treatment period.
  • FIG. 16 is a graph depicting the results in Table 5 for S. aureaus for each of the 10 dosing regimens (x-axis), where the y-axis represents the fraction of simulated patients having a plasma concentration of ceftriaxone above the MIC for S. aureaus for greater than 70% of the 72 hour treatment period.
  • FIG. 17 is a graph depicting the results in Table 5 for P. aeruginosa for each of the 10 dosing regimens (x-axis), where the y-axis represents the fraction of simulated patients having a plasma concentration of ceftriaxone above the MIC for P. aeruginosa for greater than 70% of the 72 hour treatment period.
  • FIG. 18 is a graph depicting the results in Table 5 for B.fragilis for each of the 10 dosing regimens (x-axis), where the y-axis represents the fraction of simulated patients having a plasma concentration of ceftriaxone above the MIC for B.fragilis for greater than 70% of the 72 hour treatment period.
  • a triphasic dosing regimen of a time-dependent antibiotic for example, a beta-lactam such as ceftriaxone
  • a daily triphasic dosing regimen can achieve a prolonged plasma concentration of the time-dependent antibiotic above the MIC in a patient.
  • the total time of administration can occur over about 6 hours to about 12 hours. Consequently, the triphasic dosing regimen can be subcutaneously administered conveniently via a micropump or patch pump device, which can be worn during administration and then removed for daily device-free time for the patient.
  • the triphasic (and biphasic) dosing regimen concept can apply equally to administering intravenously a time-dependent antibiotic, although the need to be connected to a source of IV fluid containing the time-dependent antibiotic would be a limitation not present when a wearable micropump or patch pump device is used. Nevertheless, the use of the triphasic dosing regimen administered via an IV can afford a patient about 8 to about 18 hours of needle-free time for attending to daily activities.
  • a biphasic dosing regimen of the present teachings can include
  • a biphasic closing regimen typically includes a maintenance or continuous phase, and a pre-removal or end bolus phase.
  • compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited process steps.
  • an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.
  • molecular weight is provided and not an absolute value, for example, of a polymer, then the molecular weight should be understood to be an average molecule weight, unless otherwise stated or understood from the context.
  • values are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges and any combination of the various endpoints of such groups or ranges.
  • an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40
  • an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, and 20.
  • patient refers to a mammal, such as a human.
  • a "compound” refers to the compound itself and its pharmaceutically acceptable salts, hydrates and esters, and biological derivatives, unless otherwise understood from the context of the description or expressly limited to one particular form of the compound, i.e., the compound itself, or a
  • a compound of the present teachings can be a time-dependent antibiotic such as beta-lactam antibiotic.
  • Particular compounds of the present teachings include ceftriaxone and ertapenem.
  • a “time-dependent antibiotic” refers to an antibiotic whose microorganism killing response is dependent on time, i.e., its bactericidal activity continues as long as the plasma concentration is greater than the minimum bactericidal concentration or the minimum inhibitory concentration ("MIC"). Unlike "concentration- dependent" antibiotics, a higher concentration of a time-dependent antibiotic does not result in increased effectiveness. Accordingly, for a time-dependent antibiotic, its plasma concentration should be maintained over the MIC for an organism to be treated for as long as possible and ideally, the entire time interval between repetitive doses.
  • time-dependent antibiotics includes beta-lactams (" ⁇ -lactams”), clindamycin, macrolides such as erythromycin, clarithromycin and vancomycin, and oxazolidinones such as linezolid.
  • ⁇ -lactams include penicillin derivatives (penams), cephalosporins (cephems), monobactams, and carbapenems.
  • the ⁇ -lactam is ceftriaxone.
  • the ⁇ - lactam is a carbapenem, for example, imipenum, meropenem, ertapenem, doripenem, panipenem/betamipron, or biopenem.
  • compositions such as antibiotic compositions that include at least one compound described herein such as a time-dependent antibiotic or a therapeutic combination, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • pharmaceutically acceptable carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington: The Science and Practice of Pharmacy, 20th edition, ed. Alfonso R. Gennaro, Lippincott Williams & Wilkins, Baltimore, MD (2000).
  • therapeutic combination refers to a combination of one or more active drug substances, i.e., compounds having a therapeutic utility such as antibiotics.
  • each such compound, one of which is a time-dependent antibiotic, in a therapeutic combination can be present in a pharmaceutical formulation comprising that compound and a pharmaceutically acceptable carrier.
  • the compounds in a therapeutic combination can be administered simultaneously, together or separately, or separately at different times, as part of a regimen of the present teachings.
  • pharmaceutically acceptable refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with an active ingredient. Accordingly,
  • pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
  • Time-dependent antibiotics and therapeutic combinations administered in accordance with the present teachings can be useful for treating a pathological condition or disorder such as the presence of an undesirable microorganism in a patient, for example, a human.
  • treating refers to partially or completely alleviating and/or ameliorating the condition and/or symptoms thereof.
  • Time-dependent antibiotics and therapeutic combinations can be administered via a triphasic or biphasic dosing regimen alone or in combination with other
  • therapeutical ly-effective compounds or therapies for the treatment of a pathological condition or disorder.
  • therapeutical ly-effective refers to a substance or an amount that elicits a desirable biological activity or effect.
  • an effective dosage can vary depending upon many factors such as the particular time-dependent antibiotic used, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated.
  • a time-dependent antibiotic can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications.
  • the dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician.
  • the variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.
  • the time above the MIC a time-dependent antibiotic is in a patient's system can be increased, for example, compared to known and conventional treatment regimens.
  • the methods generally include administering the time-dependent antibiotic to a patient in two or three dosing phases over a period of less than 24 hours.
  • the total time of administration can be about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-14 hours, or about 14-16 hours.
  • methods of administering a time-dependent antibiotic to a patient can include administering to a patient about 15% to about 35% of a daily dose of a time-dependent antibiotic during a first dosing period, where the first dosing period is about 3% to about 17% of a total time of administration;
  • methods of administering a time-dependent antibiotic to a patient can include administering to a patient a first dose of a time-dependent antibiotic sufficient to provide a plasma concentration of the antibiotic above a minimum inhibitory concentration, where administering the first dose occurs over a first dosing period of about 3% to about 17% of a total time of administration;
  • administering to the patient a second dose of the antibiotic sufficient to maintain the plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at least 50% of a second dosing period, where administering the second dose occurs over the second dosing period of about 66% to about 94% of the total time of administration; and administering to the patient a third dose of the time- dependent antibiotic sufficient to maximize a plasma concentration of the time- dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic in step (a) and in step (b), where administering the third dose occurs over a third dosing period of about 3% to about 17% of the total time of administration.
  • the sum of the first, second and third doses can equal a daily dose of the time- dependent antibiotic.
  • the total time of administration can be less than about 16 hours.
  • the total time of administration can be between about 6 to about 8 hours, between about 8 to about 10 hours, between about 10 to about 12 hours, between about 12 to about 14 hours, or between about 14 to about 16 hours.
  • the total time of administration can be about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, or about 16 hours.
  • methods of administering a time-dependent antibiotic to a patient can include administering to a patient about 15% to about 35% of a daily dose of a time-dependent antibiotic for a first dosing period, where the first dosing period is about 15 minutes to about 60 minutes; administering to the patient about 15% to about 40% of the daily dose of the time-dependent antibiotic for a second dosing period, where the second dosing period is about 4 hours to about 15.5 hours; and administering to the patient about 25% to about 70% of the daily dose of the time-dependent antibiotic for a third dosing period, where the third dosing period is about 15 minutes to about 60 minutes.
  • methods of administering a time-dependent antibiotic to a patient can include administering to a patient a first dose of a time-dependent antibiotic sufficient to provide a plasma concentration of the antibiotic above a minimum inhibitory concentration, where administering the first dose occurs over a first dosing period of about 15 minutes to about 60 minutes;
  • administering to the patient a second dose of the time-dependent antibiotic sufficient to maintain the plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at least 50% of a second dosing period, where administering the second dose occurs over the second dosing period of about 4 hours to about 15.5 hours; and administering to the patient a third dose of the time- dependent antibiotic sufficient to maximize a plasma concentration of the time- dependent antibiotic as compared to the plasma concentration of the time-dependent antibiotic during the first and second dosing periods, where administering the third dose occurs over a third dosing period of about 15 minutes to about 60 minutes.
  • the sum of the first, second and third doses can equal a daily dose of the time-dependent antibiotic.
  • the first phase (dosing period) and/or the second phase (dosing period) can include administering to a patient about 20% to about 30%, or about 23% to about 27% of a daily dose of a time-dependent antibiotic.
  • the third phase can include administering to a patient about 30% to about 65%, about 40% to about 60%, or about 47% to about 53% of a daily dose of a time-dependent antibiotic.
  • the first dosing period and/or the third dosing period can be between about 15 minutes to about 45 minutes, or between about 15 minutes to about 30 minutes.
  • the second dosing period can be about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 1 1 hours, about 1 1.5 hours, or more.
  • the first dosing period and/or the third dosing period can be between about 4% to about 12%, between about 4% to about 10%, or between about 4% to about 8% of a total time of administration.
  • the second dosing period can be between about 75% to about 94%, between about 80% to about 93%, or between about 83% to about 92% of the total time of administration.
  • the second dose of the time-dependent antibiotic can be sufficient to maintain the plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at least about 60%, about 70%, about 80%, about 90%, about 95%, or about 98% or more of the second dosing period.
  • methods of administering a time-dependent antibiotic to a patient can include administering to a patient about 25% to about 75% of a daily dose of a time-dependent antibiotic during a first dosing period, where the first dosing period is about 83% to about 96% of a total time of administration; and administering to the patient about 25% to about 75% of the daily dose of the time-dependent antibiotic for a second dosing period, where the second dosing period is about 4% to about 17% of the total time of administration.
  • administering a time-dependent antibiotic to a patient can include administering to a patient about 25% to about 75% of a daily dose of a time-dependent antibiotic for a first dosing period, where the first dosing period is about 5 hours to about 12 hours; and administering to the patient about 25% to about 75% of the daily dose of the time-dependent antibiotic for a second dosing period, where the second dosing period is about 15 minutes to about one hour.
  • biphasic dosing regimens about 25% to about 50%, about 50% to about 75%, about 40% to about 60%, or about 50% of a daily dose of a time-dependent antibiotic can be administered during the first dosing period and/or the second dosing period.
  • the methods of the present teachings can increase the daily time that the time-dependent antibiotic is above the minimum inhibitory concentration in the patient compared to administering intravenously or subcutaneously the daily dose of the time-dependent antibiotic over about 30 minutes.
  • the methods can increase the daily time that the time-dependent antibiotic is above the minimum inhibitory concentration in the patient compared to administering intravenously or
  • the methods can maintain a plasma concentration of the time-dependent antibiotic above the minimum inhibitory concentration for at least 70% of the time over a 24-hour period.
  • the dosing regimens of the present teachings generally can administer a daily dose or an amount sufficient for a 24-hour period
  • repeating the biphasic or triphasic dosing regimen (e.g., steps (a) and (b) or steps (a)-(c), respectively) in 24-hour intervals can achieve a plasma concentration of the time-dependent antibiotic in the patient above the minimum inhibitory concentration for at least 70% of the time over a 48-hour period, over a 72-hour period, over a 96-hour period, or longer.
  • the methods of the present teachings can include administering
  • the methods can include administering the time-dependent antibiotic or the antibiotic composition with a device in contact with the skin of the patient, such as a micropump, a patch pump device, or an injection needle of such a device or an intravenous delivery device.
  • a device in contact with the skin of the patient such as a micropump, a patch pump device, or an injection needle of such a device or an intravenous delivery device.
  • a feature of the present teachings is the ability of a patient undergoing antibiotic treatment to be device-free, for as long as possible, while maintaining sufficient levels of the time-dependent antibiotic in the patient. Accordingly, the methods of the present teachings can include (the step of) removing the device after the end of a daily dosing regimen (e.g., after step (c) of a triphasic dosing regimen, or after step (b) of a biphasic dosing regimen).
  • a daily dosing regimen e.g., after step (c) of a triphasic dosing regimen, or after step (b) of a biphasic dosing regimen.
  • the time-dependent antibiotic can be a ⁇ -lactam.
  • the ⁇ -lactam can be or includes ceftriaxone.
  • the ⁇ -lactam can be or includes ertapenem.
  • the pharmaceutical formulations or antibiotic compositions can be administered parenterally, including by infusion, injection or implantation, which includes subcutaneous administration as appropriate.
  • the time-dependent antibiotic or an antibiotic composition can be administered by, for example, subcutaneous injection or delivery, or by intravenous injection or delivery.
  • the pharmaceutical forms suitable for injection can include sterile solutions, suspensions, or dispersions such as a sterile aqueous solution.
  • the pharmaceutical form can be a sterile powder for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the pharmaceutical formulation is sterile and its viscosity permits it to flow through a syringe.
  • the pharmaceutical formulation should be stable under the conditions of manufacture and storage.
  • the pharmaceutical formulation can be preserved against the contaminating action of microorganisms such as bacteria and fungi, for example, by inclusion of a preservative. However, in some embodiments, the pharmaceutical formulation is preservative-free.
  • a sterile pharmaceutical formulation can be prepared using pharmaceutically accepted practices, for example, filtration and/or heat.
  • the carrier of a pharmaceutical formulation can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and/or vegetable oils.
  • a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and/or vegetable oils.
  • solutions, mixtures, or suspensions of a time-dependent antibiotic can be prepared in water, which can be suitably mixed with a surfactant such as hydroxyl-propylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.
  • liquid carriers for parenteral administration include water, alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil).
  • the carrier can be an oily ester such as ethyl oleate and isopropyl myristate.
  • the pharmaceutical formulations can include other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Because the pharmaceutical formulations and their intended use is with patients such as humans, each of the ingredients or compounds of a pharmaceutical formulation described herein can be a pharmaceutically acceptable ingredient or compound,
  • a number of devices have been proposed to facilitate self-administration of a pharmaceutical formulation including an antibiotic composition.
  • the device typically includes a reservoir containing, for example, pre-loaded with, the pharmaceutical formulation to be administered.
  • a micropump can provide precise subcutaneous administration of small quantities of a liquid pharmaceutical formulation. Such micropumps can be compact and portable.
  • Another type of device useful for subcutaneous delivery or administration of pharmaceutical formulations is often referred to as a patch device or a patch pump device. Patch devices usually are attached directly to the skin of a patient. See, e.g.. U.S. Patent Nos. 8,282,366 and 8,414,532 to Sensile Pat AG. After administration of the pharmaceutical formulation, the device can be removed from the skin of the patient.
  • a micropump or a patch pump device can include a reservoir containing an antibiotic composition; a subcutaneous injection needle configured for removable insertion into the skin of a patient; and a micropump having an inlet in fluid communication with the reservoir and an outlet in fluid communication with the subcutaneous injection needle.
  • the micropump or the patch pump device can include a control system configured to control the micropump to deliver the antibiotic composition from the reservoir through the subcutaneous injection needle to a patient according to any of the methods of the present teachings.
  • the micropump or the patch pump device also can include a housing for supporting the reservoir, the subcutaneous injection needle, the micropump, and the control system, when present.
  • the antibiotic composition contained within the reservoir can include at least one time-dependent antibiotic and a pharmaceutically acceptable carrier. After administration of the antibiotic composition according to the dosing regimens of the present teachings, the micropump or patch pump device is typically removed from the skin of the patient.
  • the control system can include a microprocessor programmed to carry out a method of the present teachings.
  • the control system (or the device) also can include wireless communications hardware to permit remote monitoring, control, and/or maintenance of the device and its operation.
  • control system can include a radio frequency (RF) transceiver positioned in the housing of the device, which RF transceiver can communicate with an external control and display unit that enables the remote control and verification of the pump operation, for example, by a patient.
  • the information transmitted by the control system can include an alarm signal arising from faulty operation.
  • the RF transceiver can use existing technology for keyed digital transmission to ensure the absence of interference with other RF devices. Such technology is widely available and is not further described herein.
  • the control system can include a radio frequency identification (RF1D) reader, for example, connected to the microprocessor and in wireless communication with an RFID transponder associated with the device, for example, its reservoir and/or micropump.
  • RFID transponders are known passive devices used in a number of different applications and comprise a small chip and a coil to generate electrical energy for powering the transponder from the RF field. Such transponders can be used as identification tags, for example, to verify origination and/or authenticity of the product and/or components thereof.
  • a patient can have a disease or condition that responds to time-dependent antibiotic treatment or therapy, for example, the time-dependent antibiotic can treat and/or ameliorate the symptoms of a bacterial infection.
  • the disease or condition that responds to time- dependent antibiotics can include one or more of pneumonia, meningitis, influenza, pelvic inflammatory disease, and infections of the lungs, ears, skin, urinary tract, blood, bones, joints, and abdomen.
  • PK pharmacokinetic
  • IV intravenous
  • SC subcutaneous
  • SCP biphasic and triphasic dosing regimens of the present teachings administered subcutaneous
  • IV refers to traditional IV infusion
  • SC refers to traditional SC infusion
  • SCP refers to SC infusion according to a biphasic or a triphasic dosing regimen according to the present teachings.
  • the values represent the amount, frequency, duration, and start time of subsequent doses of ceftriaxone administration, respectively.
  • MIC data for ceftriaxone were obtained from the Antimicrobial wild type distributions of microorganisms, available from EUCAST (European Committee on Antimicrobial Susceptibility Testing) at
  • Staphylococcus aureus one that was moderately resistant (Pseudomonas aeruginosa), and one that typically showed high levels of resistance (Bacteroides fragilis).
  • FIGS. 1 A-1C show the histograms of the MIC empirical distributions used in the pharmacodynamics model.
  • FIG. 2 is a schematic of the ceftriaxone pharmacokinetic model.
  • Non-compartmental pharmacokinetic parameters based on total ceftriaxone concentrations were available from Harb et al., "Safety and pharmacokinetics of subcutaneous ceftriaxone administered with or without recombinant human hyaluronidase (rHuPH20) versus intravenous ceftriaxone administration in adult volunteers," Curr. Med. Res. Opin. 26(2):279-288 (2010) ("Harb”). These data were used to facilitate modification of the model by Borner. Harb was particularly useful because it included non-compartmental results for both SC and IV ceftriaxone.
  • Dosing regimens included traditional single-phase IV infusion administration as well as single-phase (rapid), two-phase and three-phase SC infusion administration. More specifically, the two-phase SC dosing regimens of the present teachings (Dosing Regimens 5, 6 and 7) consisted of a zero order infusion for 5.5 hours, followed by an "end bolus” infusion over 0.5 hours. The three-phase SC dosing regimens of the present teachings (Dosing Regimens 8 and 9) consisted of an "initial bolus" infusion over 0.5 hours to achieve therapeutic concentrations above MIC quickly. The initial infusion was followed by a zero-order infusion (5 or 1 1 hour duration, respectively), and a subsequent 0.5 hour "end bolus.” Because "true" values of concentrations were of interest, residual error was set to zero for all simulations.
  • Table 2 presents the final pharmacokinetics model parameters used for all simulations. As described previously, these parameters were optimized by manually adjusting the parameter until the non-compartmental parameter estimates were consistent with Harb.
  • Table 3 presents the non-compartmental parameters resulting from a simulated one gram subcutaneous dose compared to results from Harb. Reasonable agreement is seen, both in the mean values and the variability (range or standard deviation).
  • Results for each of the pharmacokinetics simulations of Dosing Regimens I 10 are shown in FIGS. 3-12, respectively.
  • the upper plot of each figure shows the traces for the median plasma concentration and the 95% prediction intervals over time (72 h).
  • the lower plot of each figure shows the traces for the start time of the infusion and infusion rate over time (72 h).
  • Table 4 shows the median hours above MIC (of 72 hours), by organism.
  • Table 5 shows the fraction of patients with greater than 70% of time above MIC, by organism. Table 5. Fraction of Patients with Greater Than 70% of Time Above MIC, by organism.
  • the subcutaneous dosing regimens of the present teachings improved the time above MIC for all organisms, compared to the same total daily dose given once a day by IV or SC. More specifically, conventional rapid administration (IV or SC) and the SCP infusion regimens of the present teachings consistently resulted in plasma concentration above MIC for & aureus (FIGS. 13 and 16). At the other extreme of resistance, in the case of B.
  • the three-phase or triphasic SCP infusion regimens (Dosing Regimens 8 and 9) of the present teachings provided an additional benefit compared to a two-phase or biphasic infusion as the therapeutic
  • subcutaneous administration for example, using a wearable patch pump device, using slow and delayed infusion (biphasic or triphasic infusions over six to twelve hours) can result in improved time above MIC for three representative organisms (S. aureus, P. aeruginosa and B.fragilis) compared to conventional intravenous administration in accordance with the current prescribing information.
  • the dosing regimens of the present teachings improved the median time above MIC as well as the fraction of simulated patients who achieved at least 70% of the time above MIC for a 72-hour administration.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)

Abstract

L'invention concerne des procédés de traitement d'infections et d'autres maladies ou affections avec un régime posologique en deux phases ou en trois phases d'un antibiotique dépendant du temps, la durée totale de l'administration pouvant s'étaler sur une période de moins de 24 heures. La présente invention concerne également une micropompe ou un dispositif de pompe à patch, qui permet une perfusion sous-cutanée régulée d'un antibiotique dépendant du temps conformément aux régimes posologiques de la présente invention.
EP15870990.7A 2014-12-18 2015-12-16 Régimes posologiques en trois phases pour l'administration d'antibiotiques en fonction du temps et dispositifs associés Withdrawn EP3233063A4 (fr)

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