US20130065874A1 - Methods for treating intrapulmonary infections - Google Patents

Methods for treating intrapulmonary infections Download PDF

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US20130065874A1
US20130065874A1 US13/607,138 US201213607138A US2013065874A1 US 20130065874 A1 US20130065874 A1 US 20130065874A1 US 201213607138 A US201213607138 A US 201213607138A US 2013065874 A1 US2013065874 A1 US 2013065874A1
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Prior art keywords
ceftolozane
tazobactam
infection
pharmaceutical composition
elf
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Gurudatt A. Chandorkar
Jennifer A. Huntington
Tara Parsons
Obiamiwe C. Umeh
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Calixa Therapeutics Inc
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Cubist Pharmaceuticals LLC
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Priority to US13/607,138 priority Critical patent/US20130065874A1/en
Application filed by Cubist Pharmaceuticals LLC filed Critical Cubist Pharmaceuticals LLC
Assigned to ROYAL BANK OF CANADA, AS ADMINISTRATIVE AGENT reassignment ROYAL BANK OF CANADA, AS ADMINISTRATIVE AGENT SECURITY AGREEMENT Assignors: ADOLOR CORPORATION, CALIXA THERAPEUTICS, INC., CUBIST PHARMACEUTICALS HOLDINGS, INC., CUBIST PHARMACEUTICALS U.S., CUBIST PHARMACEUTICALS, INC.
Publication of US20130065874A1 publication Critical patent/US20130065874A1/en
Assigned to CUBIST PHARMACEUTICALS, INC. reassignment CUBIST PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHANDORKAR, GURUDATT A., HUNTINGTON, JENNIFER A., PARSONS, Tara, UMEH, OBIAMIWE C.
Priority to US14/512,608 priority patent/US9724353B2/en
Assigned to CALIXA THERAPEUTICS, INC. reassignment CALIXA THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CUBIST PHARMACEUTICALS, INC.
Priority to US14/550,125 priority patent/US20150080360A1/en
Assigned to ADOLOR CORPORATION, CUBIST PHARMACEUTICALS, INC., CALIXA THERAPEUTICS, INC. reassignment ADOLOR CORPORATION RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: ROYAL BANK OF CANADA, AS ADMINISTRATIVE AGENT
Priority to US15/629,360 priority patent/US10028963B2/en
Priority to US16/016,524 priority patent/US20180296567A1/en
Abandoned legal-status Critical Current

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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
    • A61K31/33—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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This disclosure relates to the treatment of intrapulmonary bacterial infections, including the treatment of nosocomial pneumonia infections, with a cephalosporin.
  • cephalosporin (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureidol-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-RZ)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid (also referred to as “CXA-101” and previously designated FR264205) is an antibacterial agent.
  • CXA-101 can be provided as the compound shown in FIG. 1 .
  • CXA-101 The antibacterial activity of CXA-101 is believed to result from its interaction with penicillin binding proteins (PBPs) to inhibit the biosynthesis of the bacterial cell wall which acts to stop bacterial replication.
  • CXA-101 can be combined (e.g., mixed) with a ⁇ -lactamase inhibitor (“BLI”), such as tazobactam.
  • BLI ⁇ -lactamase inhibitor
  • Tazobactam is a BLI against Class A and some Class C ⁇ -lactamases, with well established in vitro and in vivo efficacy in combination with active ⁇ -lactam antibiotics.
  • the combination of CXA-101 and tazobactam in a 2:1 weight ratio is an antibiotic pharmaceutical composition (“CXA-201”) for parenteral administration.
  • CXA-201 displays potent antibacterial activity in vitro against common Gram-negative and selected Gram-positive organisms.
  • CXA-201 is a combination antibacterial with activity against many Gram-negative pathogens known to cause intrapulmonary infections, including nosocomial pneumonia caused by P. aeruginosa.
  • Intrapulmonary infections such as nosocomial pneumonia, remain a major cause of morbidity and mortality, especially infections caused by drug resistant pathogens such as P. aeruginosa.
  • One challenge in treating intrapulmonary infections with systemic administration of an antibiotic is determining the antibiotic dose that will provide a therapeutically safe and effective concentration of the antibiotic at the site of an infection on the mucosal side of the bronchi in the lung (i.e., in the bronchial secretions).
  • Many antibiotics diffuse poorly from the bloodstream across the bronchi [e.g., Pennington, J.
  • ELF epithelial lining fluid
  • the concentration of antibiotics measured in the ELF of the lung has varied widely.
  • the reported penetration ratio of telavancin in healthy human volunteers ranges widely between 0.43 and 1.24 (Lodise, Gottokd, Drusano, 2008 Antimicrobial Agents and Chemotherapy).
  • predicting the penetration of a drug into the ELF a priori based on the structure, molecular weight, size and solubility is difficult due to the limited data available on the effect of physicochemical properties on the lung penetration of drugs.
  • the efficacy of a particular drug in treating intrapulmonary infections cannot be predicted solely on the basis of data, such as in vitro data relating to the activity of that drug against a particular bacterium, which does not give any indication as whether the drug will accumulate at a therapeutically safe and effective concentration at the site of an infection on the mucosal side of the bronchi in the lung (i.e., in the bronchial secretions).
  • data such as in vitro data relating to the activity of that drug against a particular bacterium, which does not give any indication as whether the drug will accumulate at a therapeutically safe and effective concentration at the site of an infection on the mucosal side of the bronchi in the lung (i.e., in the bronchial secretions).
  • tigicycline a glycylcycline antimicrobial
  • aeruginosa aeruginosa
  • it has been approved by the FDA for the treatment of complicated skin and skin structure infections, complicated intra-abdominal infections, and community acquired pneumonia.
  • tigicycline is not approved for the treatment of nosocomial pneumonia, in view of an increased mortality risk associated with the use of tigicycline compared to other drugs in patients treated for nosocomial pneumonia.
  • the present invention provides methods for treating intrapulmonary infections, including nosocomial pneumonia, with systemic administration of a pharmaceutical composition comprising ceftolozane.
  • the invention is based in part on results from a human clinical study designed to assess the ELF penetration of CXA-201 in comparison to piperacillin/tazobactam, indicated for the treatment of nosocomial pneumonia.
  • the study described herein quantified the penetration of CXA-201 into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC(ELF)/AUC(plasma) ratio).
  • CXA-201 penetrated well into the ELF of healthy volunteers compared to piperacillin/tazobactam, an agent widely used for treatment of lower respiratory infections.
  • the intrapulmonary pharmacokinetics measured in the study supports the use of CXA-201 as a parenteral (e.g., intravenous) antibiotic for treatment of intrapulmonary infections, such as nosocomial pneumonia or other lower respiratory tract infections.
  • FIG. 1 is the chemical structure of a salt of ceftolozane hydrogen sulfate salt.
  • FIG. 2A is a graph showing the ELF Concentration vs. Time Profile for ceftolozane hydrogen sulfate salt (Median and Range) for CXA-201.
  • FIG. 2B is a graph showing the ELF Concentration vs. Time Profile for Tazobactam (Median and Range) for CXA-201.
  • FIG. 3A is a graph showing the (Comparative) ELF Concentration vs. Time Profile for Piperacillin (Median and Range) for a piperacillin/tazobactam comparator (ZOSYN®).
  • FIG. 3B is a graph showing the (Comparative) ELF Concentration vs. Time Profile for Tazobactam (Median and Range) for a piperacillin/tazobactam comparator (ZOSYN®).
  • FIGS. 4A and 4B are synthetic schemes for preparing ceftolozane hydrogen sulfate salt.
  • ceftolozane means CXA-101 in a free-base or salt form, preferably a hydrogen sulfate form (illustrated in FIG. 1 ).
  • ceftolozane is CXA-101 in its free-base form.
  • ceftolozane is CXA-101 in its salt form, preferably a hydrogen sulfate form.
  • ceftolozane (in free base or salt form, preferably hydrogen sulfate form) and tazobactam are in a 2:1 (ceftolozane:tazobactam) weight ratio.
  • methods of treating intrapulmonary infections, including nosocomial pneumonia with systemic administration of a pharmaceutical composition comprising ceftolozane hydrogen sulfate and tazobactam in a 2:1 weight ratio.
  • ceftolozane hydrogen sulfate and tazobactam in a 2:1 weight ratio.
  • the combination of ceftolozane hydrogen sulfate and tazobactam in a 2:1 weight ratio is referred to herein and in the examples as “CXA-201.”
  • the invention provides a method of treating an intrapulmonary infection comprising administering a therapeutically effective amount of a pharmaceutical composition comprising ceftolozane.
  • the method may comprise administering a pharmaceutical composition comprising ceftolozane in combination with tazobactam.
  • the invention provides a method of treating an intrapulmonary infection comprising the step of intravenously administering about every 8 hours to a subject in need thereof a pharmaceutical composition comprising 3.0 g of ceftolozane.
  • the method may comprise administering a pharmaceutical composition comprising ceftolozane in combination with tazobactam.
  • the method comprises administering CXA-201 and the infection comprises Gram-negative bacteria.
  • the invention provides a method of treating an intrapulmonary infection comprising the step of intravenously administering every 8 hours to a subject in need thereof a pharmaceutical composition comprising 3.0 g of ceftolozane.
  • the invention provides a method of providing tazobactam or ceftolozane in the epithelial lining fluid of a subject in an amount effective to treat an intrapulmonary infection, comprising the step of intravenously administering to the subject a pharmaceutical composition comprising ceftolozane.
  • the method may comprise administering a pharmaceutical composition further comprising tazobactam, optionally wherein the pharmaceutical composition is CXA-201.
  • the method may comprise administering about 1.5 g of ceftolozane and tazobactam in total every 8 hours.
  • the amount of the ceftolozane in the ELF of the subject effective to treat an intrapulmonary infection is at least about 8 ⁇ g/ml.
  • the ELF concentration of ceftolozane in the ELF may reach at least about 8 ⁇ g/ml after administration of the pharmaceutical composition.
  • the subject is typically a human having, or believed to be at risk of having, nosocomial pneumonia.
  • the subject (or patient) may, in some embodiments, have ventilator acquired pneumonia or hospital acquired pneumonia.
  • the invention provides the use of ceftolozane in the manufacture of a medicament for the treatment of an intrapulmonary infection comprising administering a therapeutically effective amount of a pharmaceutical composition comprising the ceftolozane.
  • the use may comprise administering the pharmaceutical composition comprising ceftolozane, in combination with tazobactam.
  • the invention provides the use of ceftolozane in the manufacture of a medicament for the treatment of an intrapulmonary infection comprising intravenously administering a pharmaceutical composition comprising 3.0 g of the ceftolozane every 8 hours to a subject in need thereof.
  • the use may comprise administering the pharmaceutical composition comprising ceftolozane in combination with tazobactam.
  • the use comprises administering ceftolozane and tazobactam and the infection comprises Gram-negative bacteria.
  • the invention provides the use of ceftolozane in the manufacture of a medicament for the treatment of an intrapulmonary infection comprising intravenously administering a pharmaceutical composition comprising the ceftolozane, wherein tazobactam or ceftolozane is provided in the epithelial lining fluid of a subject in an amount effective to treat the intrapulmonary infection.
  • the use may comprise administering a pharmaceutical composition further comprising tazobactam, optionally wherein the pharmaceutical composition is CXA-201.
  • the use may comprise administering about 1.5 g of ceftolozane and tazobactam every 8 hours.
  • the amount of the ceftolozane in the ELF of the subject effective to treat an intrapulmonary infection is at least about 8 ⁇ g/ml.
  • the ELF concentration of ceftolozane in the ELF may reach at least about 8 ⁇ g/ml after administration of the pharmaceutical composition.
  • the subject is typically a human having, or believed to be at risk of having, nosocomial pneumonia.
  • the subject (or patient) may, in some embodiments, have ventilator acquired pneumonia or hospital acquired pneumonia.
  • the pharmaceutical composition may be administered parenterally.
  • the pharmaceutical composition may be administered intravenously.
  • the pharmaceutical composition is intravenously administered about once every 8 hours as an infusion.
  • the pharmaceutical composition may be intravenously administered as a 60-minute infusion.
  • the intrapulmonary infection may be an infection in the lung.
  • the intrapulmonary infection may be pneumonia.
  • the intrapulmonary infection is nosocomial pneumonia.
  • the intrapulmonary infection may comprise Pseudomonas aeruginosa, Enterobacteriaceae, or a combination thereof.
  • the intrapulmonary infection comprises Pseudomonas aeruginosa.
  • the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for CXA-201 of ⁇ 8 ⁇ g/ml.
  • the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane of ⁇ 8 ⁇ g/ml.
  • the invention provides ceftolozane, for use in a method of treating an intrapulmonary infection.
  • the ceftolozane is parenterally administered.
  • the ceftolozane is intravenously administered.
  • the ceftolozane is administered about once every 8 hours as an infusion.
  • the ceftolozane is intravenously administered as a 60-minute infusion.
  • the ceftolozane is for use in a method of treating an intrapulmonary infection wherein the intrapulmonary infection comprises an infection in the lung.
  • the intrapulmonary infection may be pneumonia.
  • the ceftolozane is for use in a method of treating nosocomial pneumonia.
  • the intrapulmonary infection may comprise Pseudomonas aeruginosa, Enterobacteriaceae, or a combination thereof.
  • the intrapulmonary infection comprises Pseudomonas aeruginosa.
  • the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane and tazobactam of ⁇ 8 ⁇ g/ml.
  • the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane of ⁇ 8 ⁇ g/ml.
  • the invention also provides ceftolozane, for use in a method of treating an intrapulmonary infection, comprising administration of ceftolozane in combination with tazobactam.
  • the ceftolozane and/or tazobactam is parenterally administered.
  • the ceftolozane and/or tazobactam is intravenously administered.
  • the ceftolozane and/or tazobactam is administered about once every 8 hours as an infusion.
  • the ceftolozane and/or tazobactam is intravenously administered as a 60-minute infusion.
  • both the ceftolozane and tazobactam are parenterally administered. In another embodiment, both the ceftolozane and tazobactam are intravenously administered. In some embodiments, both the ceftolozane and tazobactam are administered about once every 8 hours as an infusion. In some embodiments, both the ceftolozane and tazobactam are intravenously administered as a 60-minute infusion. In one embodiment, the ceftolozane is for use in a method of treating an intrapulmonary infection wherein the intrapulmonary infection comprises an infection in the lung. The intrapulmonary infection may be pneumonia.
  • the ceftolozane is for use in a method of treating nosocomial pneumonia.
  • the intrapulmonary infection may comprise Pseudomonas aeruginosa, Enterobacteriaceae, or a combination thereof.
  • the intrapulmonary infection comprises Pseudomonas aeruginosa.
  • the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane and tazobactam of ⁇ 8 ⁇ g/ml.
  • the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane of ⁇ 8 ⁇ g/ml.
  • the invention provides tazobactam, for use in a method of treating an intrapulmonary infection, comprising administration of tazobactam in combination with ceftolozane.
  • the tazobactam and/or ceftolozane is parenterally administered.
  • the tazobactam and/or ceftolozane is intravenously administered.
  • the tazobactam and/or ceftolozane is administered about once every 8 hours as an infusion.
  • the tazobactam and/or ceftolozane is intravenously administered as a 60-minute infusion.
  • both the tazobactam and ceftolozane are parenterally administered. In another embodiment, both the tazobactam and ceftolozane are intravenously administered. In another embodiment, both the tazobactam and ceftolozane are administered about once every 8 hours as an infusion. In another embodiments, both the tazobactam and ceftolozane are intravenously administered as a 60-minute infusion.
  • the tazobactam is for use in a method of treating an intrapulmonary infection wherein the intrapulmonary infection comprises an infection in the lung.
  • the intrapulmonary infection may be pneumonia.
  • the tazobactam is for use in a method of treating nosocomial pneumonia.
  • the intrapulmonary infection may comprise Pseudomonas aeruginosa, Enterobacteriaceae, or a combination thereof.
  • the intrapulmonary infection comprises Pseudomonas aeruginosa.
  • the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane and tazobactam of ⁇ 8 ⁇ g/ml.
  • the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane of ⁇ 8 ⁇ g/ml.
  • the invention provides ceftolozane and tazobactam, as a combined preparation for simultaneous, separate or sequential use in a method of treating an intrapulmonary infection.
  • the ceftolozane and tazobactam are parenterally administered.
  • the ceftolozane and tazobactam are intravenously administered.
  • the ceftolozane and tazobactam are administered about once every 8 hours as an infusion.
  • the ceftolozane and tazobactam are intravenously administered as a 60-minute infusion.
  • the ceftolozane and tazobactam are for use in a method of treating an intrapulmonary infection wherein the intrapulmonary infection comprises an infection in the lung.
  • the intrapulmonary infection may be pneumonia.
  • the ceftolozane and tazobactam are for use in a method of treating nosocomial pneumonia.
  • the intrapulmonary infection may comprise Pseudomonas aeruginosa, Enterobacteriaceae, or a combination thereof.
  • the intrapulmonary infection comprises Pseudomonas aeruginosa.
  • the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane and tazobactam of ⁇ 8 ⁇ g/ml.
  • the intrapulmonary infection may comprise a pathogen with minimum inhibitory concentration for ceftolozane of ⁇ 8 ⁇ g/ml.
  • the invention provides ceftolozane for use in a method of providing tazobactam or ceftolozane in the epithelial lining fluid of a subject in an amount effective to treat an intrapulmonary infection, comprising the step of intravenously administering ceftolozane.
  • ceftolozane is administered in combination with tazobactam.
  • CXA-201 is administered.
  • about 1.5 g of ceftolozane and tazobactam is administered every 8 hours.
  • the amount of the ceftolozane in the ELF of the subject effective to treat an intrapulmonary infection is at least about 8 ⁇ g/ml.
  • the ELF concentration of ceftolozane in the ELF may reach at least about 8 ⁇ g/ml after administration of the ceftolozane.
  • the subject is typically a human having, or believed to be at risk of having, nosocomial pneumonia.
  • the subject (or patient) may, in some embodiments, have ventilator acquired pneumonia or hospital acquired pneumonia.
  • the safe and effective treatment of intrapulmonary infection with CXA-201 includes administration of an amount of the CXA-201 selected to provide a therapeutically effective dose of the CXA-201 antibiotic in the epithelial lining fluid (ELF).
  • ELF epithelial lining fluid
  • the penetration of CXA-201 into the ELF compared to a piperacillin/tazobactam comparator was assessed in a Phase 1 clinical study in healthy adult volunteers.
  • the piperacillin/tazobactam comparator contained piperacillin/tazobactam in an 8:1 weight ratio with a total of 2.79 mEq of sodium per gram of piperacillin, FDA approved under the tradename ZOSYN® (“Zosyn”).
  • the study results evaluate the penetration of intravenously administered CXA-201 into healthy human lungs, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC(ELF)/AUC(plasma)ratio).
  • AUC area under the concentration-time curve
  • a 4.5 g amount of piperacillin/tazobactam incorporates the same dose of tazobactam (0.5 g) as 1.5 g of CXA-201.
  • a multiple-dose regimen was used in this study to ensure that the concentrations of the analytes reached steady-state in both plasma and ELF prior to assessment. Healthy volunteers were chosen to standardize the subject population and minimize the variability associated with using actively ill patients. The objectives of the study included: (1) determination and comparison of the ELF to plasma concentration ratios of multiple-doses of intravenous CXA-201 compared to piperacillin/tazobactam in healthy adult volunteers, and (2) assessment of the safety and tolerability of multiple-doses of intravenous CXA-201 in healthy adult volunteers.
  • BAL bronchoalveolar lavage
  • Plasma and BAL datapoints were used to construct one concentration-time profile in the ELF using the mean concentrations at each time point.
  • a single ELF sample was obtained by bronchoalveolar lavage (BAL) from each healthy volunteer at one of 5 scheduled time points (5 subjects/time point/treatment group).
  • the ELF to plasma concentrations of multiple-doses was determined.
  • Serial plasma samples were collected pre- and post-treatment over a 6-hour (piperacillin/tazobactam) or 8-hour (CXA-201) time period.
  • Urea levels in the plasma and BAL were used to calculate the ELF drug concentrations (see Table 1).
  • Pharmacokinetic parameters for ELF were calculated by non-compartmental analysis using the mean concentrations at each time point.
  • the intrapulmonary penetration of CXA-201 into the ELF was determined by dividing the ELF AUC 0 -t by mean plasma AUC 0 -t.
  • the concentration of CXA-201 and piperacillin/tazobactam in ELF were estimated from the concentration of drug in BAL fluid, the volume of BAL fluid collected, and the ratio of urea concentration in BAL fluid to that in plasma. Calculation of ELF volume was determined by the urea dilution method, using urea as an endogenous marker of ELF recovered by BAL. Concentration of CXA-201 and piperacillin/tazobactam in ELF was estimated from the concentration of drug in BAL fluid, the volume of BAL fluid collected, and the ratio of urea concentration in BAL fluid to that in plasma. The following formulas represent these calculations:
  • CXA-201 (CXA/T) [CXA/T] BAL ⁇ V BAL /V ELF
  • [CXAM BAL is the concentration of CXA-201 in BAL fluid; V BAL is the volume of aspirated BAL fluid (total); V ELF is V BAL ⁇ [urea] BAL /[urea] plasma , where [urea] BAL is the concentration of urea in the BAL fluid (supernatant) and [urea] plasma is the concentration of urea in the plasma specimens.
  • [PIP/T] BAL is the concentration of piperacillin/tazobactam in BAL fluid
  • V BAL is the volume of aspirated BAL fluid (total)
  • V ELF is V BAL ⁇ [urea] BAL /[urea] plasma , where [urea] BAL is the concentration of urea in the BAL fluid (supernatant) and [urea] plasma is the concentration of urea in the plasma specimens.
  • the ELF concentration vs. time profiles for ceftolozane and tazobactam components of CXA-201 are shown in FIGS. 2A and 2B , respectively.
  • Comparative data showing the ELF concentration vs. time profiles for piperacillin and tazobactam components of the comparator drug are shown in FIGS. 3A and 3B , respectively.
  • the ELF to plasma penetration ratios are shown in Table 2.
  • the PK parameters were determined by non-compartmental PK analysis. PHOENIX® WinNonlin v 6.1 (PHARSIGHT®, Mountain View, Calif.) was used for the derivation of all PK individual measures for each subject.
  • the PK parameters for ELF were calculated by taking the mean concentrations of the 5 subjects at each time point and constructing a single profile over the duration of sampling. In the event that the urea concentrations determined in plasma or ELF were below quantifiable limits, thereby providing only an estimate of concentration, those values were not used in the calculation of mean concentration at that time point.
  • the ceftolozane, piperacillin, and tazobactam PK parameters that were computed in plasma and ELF were:
  • the ELF/plasma AUC ratio for the ceftolozane component of CXA-201 was 0.48, compared to 0.26 for the piperacillin component of the comparator drug (piperacillin/tazobactam).
  • the ELF/plasma AUC ratio for tazobactam was 0.44 and 0.54 when given as part of CXA-201 and piperacillin/tazobactam, respectively.
  • the ELF concentrations of ceftolozane exceeded 8 ⁇ g/mL for 60% of the 8-hour dosing interval.
  • the plasma and ELF concentrations of tazobactam when given as piperacillin/tazobactam was approximately 2-fold higher than when an equivalent dose was given as CXA-201.
  • ceftolozane and tazobactam i.e., administered as CXA-201 penetrated well into the ELF of healthy volunteers compared to piperacillin/tazobactam, an agent widely used for treatment of lower respiratory infections.
  • CXA-201's intrapulmonary pharmacokinetics support use of CXA-201 as a parenteral (e.g., intravenous) antibiotic for treatment of lower respiratory tract infections, including infections caused by pathogens with minimum inhibitory concentrations of ⁇ 8 ⁇ g/ml.
  • the concentrations of ceftolozane in ELF exceeded 8 ⁇ g/mL, a concentration that inhibits 99% of P. aeruginosa, for approximately 60% of the 8-hour dosing interval for the CXA-201 regimen of 1.5 grams every eight hours as a 60 minute infusion.
  • TEAEs treatment-emergent AEs
  • a Monte Carlo simulation was performed based on clinical trial data to predict an effective CXA-201 dose for treating nosocomial pneumonia using PHOENIX® NLME (PHARSIGHT®, Mountain View, Calif.) software, a tool for data processing and modeling for population PK/PD analysis.
  • a population pharmacokinetic (PK) model was developed using the CXA-201 plasma concentration versus time data from a previously conducted Phase 2 study in patients with complicated intra abdominal infections. Estimates of clearance and volume of distribution along with the associated inter-individual variability were obtained from these analyses.
  • the outputs from the PK population model served as inputs for a clinical trial simulation performed using PHARSIGHT® Trial Simulator (PHARSIGHT®) software, a tool for defining and testing interactive drug models, exploring and communicating study design attributes, and performing statistical and sensitivity analysis through graphical and statistical summaries.
  • PHARSIGHT® PHARSIGHT® Trial Simulator
  • an ELF/Plasma AUC ratio of 0.48 for ceftolozane (modeled as a numerical range of 0.25-0.65) calculated from the ceftolozane ELF study mentioned above was used to generate a random/Plasma AUC ratio from the range 0.25-0.65 for each simulated patient. This range reflects a conservative estimate of the potential distribution in a patient population.
  • the model simulated plasma and ELF concentration of CXA-201 versus time profiles for 1,000 hypothetical clinical trial patients with nosocomial pneumonia.
  • the model evaluated the probability of clinical success of the 3.0 g every 8 hour (q8h) dose of CXA-201 against three key pathogens in nosocomial pneumonia.
  • the MIC distribution for these pathogens was imputed from 2008 United States surveillance data.
  • Clinical success was defined as the achievement of an ELF or plasma concentration of ceftolozane higher than the MIC(s) of the lower respiratory pathogen(s) for a given patient.
  • the relavent PK/PD driver for CXA-201 is the percentage of time above MIC during the dosing interval.
  • the target is to achieve concentrations that exceed the MIC of the pathogen for 45-50% of the time between each q8H dose.
  • a threshold of 50% time above the minimum inhibitory concentration [T>MIC] on Day 7 of treatment was used.
  • Plasma and ELF concentrations were estimated at 15 time-points post-administration on Day 7 when dosed every 8 hours. The results of these simulations are shown in Table 5.
  • CXA-201 can be prepared by combining ceftolozane and tazobactam in a 2:1 weight ratio.
  • CXA-201 can be obtained using methods described in U.S. Pat. No. 7,129,232 and Toda et al., “Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: Discovery of FR264205, ” Bioorganic & Medicinal Chemistry Letters, 18, 4849-4852 (2008), incorporated herein by reference in its entirety.
  • ceftolozane can be obtained by the synthetic schemes of FIGS. 4A and 4B . Referring to FIGS. 4A and 4B .
  • ceftolozane can be performed via activation of the thiadiazolyl-oximinoacetic acid derivative (I) with methanesulfonyl chloride and K 2 CO 3 in DMA at 10° C., followed by coupling with the 7-aminocephem (II) by means of Et 3 N in cold EtOAc/H 2 O, affords amide (III) (1).
  • the antibacterial activity of the CXA-201 or other compounds can be measured by the minimum inhibitory concentrations (MIC) of the compounds against various bacteria measured by using the broth microdilution method performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines with modifications as described below (CLSI guidelines can be derived from the CLSI document M7-A8 published in January 2009: “Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Eighth Edition”).
  • MIC minimum inhibitory concentrations
  • individual colonies can be isolated by streaking frozen glycerol material containing Staphylococcus or Pseudomonas spp. onto rich, non-selective, tryptic soy agar containing 5% sheep's blood (TSAB), and incubated at 37° C. for 18-24 hrs.
  • TSAB sheep's blood
  • CAMHB that contained compound concentrations ranging from 64-0.06 ⁇ g/mL in two-fold dilutions can also be added to the broth microdilution assay plates for a final volume 100 ⁇ L per well, therefore final culture OD 600 was approximately 0.001 and the final NaCl concentration for the MRSA strain was 2%.
  • Plates can be incubated for 18-20 hours at 37° C. with aeration (200 rpm). Following incubation, growth can be confirmed visually placing plates over a viewing apparatus (stand with a minor underneath) and then OD 600 can be measured using a SpectraMax 340PC384 plate reader (Molecular Devices, Sunnyvale, Calif.). Growth was defined as turbidity that could be detected with the naked eye or achieving minimum OD 600 of 0.1. MIC values were defined as the lowest concentration producing no visible turbidity.

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