611. Intrapulmonary Penetration of CXA-201 and Piperacillin/tazobactam in Healthy Adult Subjects
Session: Poster Abstract Session: Novel Antimicrobial Agents
Friday, October 21, 2011
Room: Poster Hall B1
Background: CXA-201 (CXA-101/tazobactam), a combination antibacterial with excellent in vitro activity against Pseudomonas aeruginosa (MIC90 = 2 μg/mL) and Enterobacteriaceae (MIC90 = 1 μg/mL), is currently being developed for treatment of serious bacterial infections. The epithelial lining fluid (ELF) penetration of CXA-201 compared to piperacillin/tazobactam (P/T) was assessed in a Phase 1 clinical study.

Methods: This was a prospective, randomized (1:1), open-label study of 50 healthy adult volunteers (HV). Each HV received 3 doses of either 1.5g CXA-201 or 4.5g P/T.  After dosing, single ELF samples were obtained by bronchoalveolar lavage (BAL) in each HV at one of 5 scheduled time points (5 subjects/time point/treatment group). Serial plasma samples were collected pre- and post-treatment over a 6-hour (P/T) or 8-hour (CXA-201) time period. Urea levels in the plasma and BAL were used to calculate the ELF drug concentrations. Pharmacokinetic parameters 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 AUC0-t by mean plasma AUC0-t.

Results: CXA-201 and P/T penetrated well into ELF.  The CXA-101 ELF/plasma AUC ratio was 0.49, compared to 0.35 for piperacillin.  The ELF concentrations of CXA-101 exceeded 8 µg/mL for 63% of the 8-hour dosing interval. The plasma concentrations for CXA-101 were consistent with those seen previously at this dose.

Conclusion: CXA-101 penetrated well into the ELF of HV compared to P/T, an agent widely used for treatment of lower respiratory infections. CXA-201’s intrapulmonary pharmacokinetics suggests potential utility as an agent for treatment of lower respiratory tract infections caused by pathogens with minimum inhibitory concentrations of ≤ 8µg/ml.


Subject Category: C. Clinical studies of bacterial infections and antibacterials including sexually transmitted diseases and mycobacterial infections (surveys, epidemiology, and clinical trials)

Gurudatt Chandorkar, PhD1, Jennifer Huntington, PharmD1, Tara Parsons1, Mark Gotfried, MD2 and Obiamiwe Umeh, MD, MSc1, (1)Cubist Pharmaceuticals, Lexington, MA, (2)Pulmonary Associates, Phoenix, AZ

Disclosures:

G. Chandorkar, Cubist Pharmaceuticals: Employee, Salary

J. Huntington, Cubist Pharmaceuticals: Employee, Salary

T. Parsons, Cubist Pharmaceuticals: Employee, Salary

M. Gotfried, Cubist Pharmaceuticals: Research Relationship, Research support
Johnson and Johnson: Research Relationship, Research support
Forest: Research Relationship, Research support

O. Umeh, Cubist Pharmaceuticals: Employee, Salary

Findings in the abstracts are embargoed until 12:01 a.m. EST Thursday, Oct. 20 with the exception of research findings presented at IDSA press conferences.