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Population pharmacokinetics of doripenem in Japanese subjects and Monte Carlo simulation for patients with renal impairment

Abstract number: P805

Matsuo Y., Ishibashi T., Kubota R., Wajima T.

Objectives: Doripenem (DRPM), a parenteral carbapenem antibiotic, exhibits broad spectrum of anti-bacterial activity against any aerobic Gram-positive and Gram-negative bacteria and anaerobes. The aim of this study was to evaluate the pharmacokinetics (PK) of DRPM using plasma concentrations in the clinical studies by means of population PK analysis. In addition, dosing regimens for patients with renal impairment were investigated by Monte-Carlo simulation.

Methods: A total of 921 plasma concentration data from 92 subjects from 8 phase 1 studies (including studies for subjects with renal impairment and elderly subjects) were used for population PK analysis. Age, body weight and renal function (creatinine clearance, CLcr) were evaluated as covariates on PK of DRPM. Model evaluation was performed using conventional diagnostic plots and a visual predictive check. Final model was used to predict plasma concentration profiles in patients using their covariates to confirm whether the model would be applied to patients. The final model was also employed to simulate the effect of renal function on PK and PK/PD parameters by means of Monte-Carlo simulations.

Results: The two compartment model well described the observed DRPM plasma concentrations. CLcr and age were found to be predictors of DRPM clearance and CLcr was the most important influencing factor on PK of DRPM, which was consistent with the previous finding that DRPM is mainly eliminated via kidney. The plasma concentration profiles simulated for patients based on the final model parameters estimated from the phase 1 data were consistent with observed data, suggesting that DRPM PK can be explained by CLcr and age, and that there was no significant PK difference between non-infected subjects and patients. Simulations suggest that 1 g every 12 hours (q12h), 0.5 g every 8 hours (q8h) and 0.25 g q8h for patients with mild, moderate and severe renal impairment, respectively, give similar exposures (AUC) and sufficient the percentage of time above minimum inhibitory concentration derived from free drug concentration (%T > MIC) in comparison with 1 g q8h for patients with normal renal function.

Conclusion: Our population PK model confirmed renal function is the most important influencing factor on PK of DRPM. Dose adjustment based on CLcr is recommended for patients with renal impairment.

Session Details

Date: 07/05/2011
Time: 00:00-00:00
Session name: Abstracts of 21st ECCMID / 27th ICC
Subject:
Location: Milan, Italy, 7 - 10 May 2011
Presentation type:
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