Background: Doripenem is a broad-spectrum carbapenem currently in development for treatment of bacterial infections. Previously, we presented a population pharmacokinetic (PK) model for doripenem in healthy subjects (ICAAC 2003, A-11). A refined PK model was developed to describe doripenem data in patients and assess the impact of subject characteristics on PK variability.
Methods: A population PK model was developed using data from Phase 1 subjects (n = 44) and Phase 2 patients (n = 107). Doripenem (250 – 1000 mg) was infused over 30 or 60 min as a single dose or either BID/TID for 7 days. Serial blood samples were collected on Days 1 and 7. Two- and three-compartment models with zero-order input and first-order elimination were evaluated. Subject demographics were evaluated as predictors of PK variability using stepwise forward selection and backward elimination.
Results: Doripenem data were similar for subjects and patients and were best described using a two-compartment model. Interindividual variability of clearance (CL), distribution clearance (Q), and the central (Vc) and peripheral (Vp) volumes were described using an exponential error model and were estimated to be 30, 61, 35, & 100 %CV, respectively. A log error model best described the residual variability. The model estimated CL to increase 11% for Days 2-7 relative to Day 1. Significant relationships were identified between CL and creatinine clearance, Vc and age, Q and weight, and Vp with both age and gender. Predicted mean Cmax and AUC0-∞ for a 500-mg dose infused over 1 hr were 20.2 μg/mL and 44.1 mg·hr/L, respectively. AUC0-∞ was ~1.5-fold and 2-fold higher for individuals with mild and moderate renal impairment, respectively, compared to young adults with normal renal function.
Conclusions: A population PK model was developed for doripenem and the impact of subject covariates was evaluated. Identification of measurable factors that significantly influence PK variability provides a predictive tool for estimating doripenem exposures and can be used for exposure response evaluations of safety and efficacy to support Phase 3 dose selection.
Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Washington, DC, October 2004
By Scott Van Wart, Sujata M. Bhavnani, Luann Phillips, Matthew A. Wikler, and Paul G. Ambrose