589. Probability of Target Attainment (PTA) of CXA-201 in Patients with Renal Hyperclearance
Session: Poster Abstract Session: Novel Antimicrobial Agents
Friday, October 21, 2011
Room: Poster Hall B1

Background: CXA-201, a novel cephalosporin (CXA-101) and β-lactamase inhibitor (tazobactam) combination, is being developed for the treatment of serious infections due to Gram-negative pathogens. Hyperclearance [creatinine clearance (CrCL) > 150 mL/min] may significantly impact the pharmacokinetics/pharmacodynamics (PK/PD) of renally excreted antibiotics by lowering drug levels below therapeutic thresholds. Failure to account for hyperclearance during dose selection may result in treatment failure and potentially lead to emergence of resistance. Thus, simulations evaluating the PK/PD of CXA-201 in critically ill (CI) patients with hyperclearance are critical to ensure adequate PTA.

 

Methods: Monte Carlo simulations to evaluate the effect of CrCL on systemic CXA-201 exposure were performed using a population PK model for CXA-201 in conjunction with a distribution of CrCL in CI patients obtained from the literature (approximately 25% of CI patients from the literature exhibited hyperclearance). The PTA for the CXA-101 component [1000 mg, 1500 mg and 2000 mg IV Q8H (1 hr infusion)] was estimated.

Results: Area under the concentration-time curve (AUC) and PTA for various doses & MICs [using a time above MIC target (T>MIC) of 40%] are presented in the following table.

 

CXA-101 (mg)

CrCL (mL/min)

AUC (g*h/mL)a

PTA 40% T>MIC 2/4/8 g/mL (%)

1000

> 90

188.6

100/100/97.6

1000

150

152.2

100/100/97.5

1500

150

228.6

100/100/99.7

2000

150

308.8

100/100/100

1000

200

125.4

100/99.6/87.7

1500

200

191.0

100/100/97.5

2000

200

254.4

100/100/99.4

1000

250

110.3

100/97.2/71

1500

250

163.5

100/99.9/92.8

2000

250

221.1

100/100/97.8

a Values reported as median

Conclusion: The simulations showed that for CrCLs up to 200 mL/min, the PTA of the 1000 mg Q8H dose of CXA-201was 99% or higher for organisms with an MIC up to 4 g/mL suggesting that the vast majority of organisms likely to be encountered in a typical nosocomial pneumonia trial would be covered. The PTA may be less than 90% when patients with a CrCL > 200 mL/min are infected with an organism whose MIC is ≥ 8 g/mL. This needs to be investigated further.


Subject Category: A. Antimicrobial agents and Resistance

Benjamin Miller, PharmD1, Mohamad-Samer Mouksassi, PharmD2, Gurudatt Chandorkar, PhD1 and Obiamiwe Umeh, MD, MSc1, (1)Cubist Pharmaceuticals, Lexington, MA, (2)Pharsight, A Certara Company, Montreal, QC, Canada

Disclosures:

B. Miller, Cubist Pharmaceuticals: Employee, Salary

M. S. Mouksassi, Pharsight: Employee, Consulting fee

G. Chandorkar, Cubist Pharmaceuticals: Employee, Salary

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.