MP11-10 CLINICAL PHARMACOKINETICS OF BETA-LACTAM ANTIBIOTICS IN PROSTATE TISSUE, AND DOSING CONSIDERATIONS FOR PROSTATITIS BASED ON SITE-SPECIFIC PHARMACODYNAMICS

Abstract

INTRODUCTION AND OBJECTIVES: Carbapenems (doripenem and meropenem) are a therapeutic option for bacterial prostatitis and antibacterial prophylaxis in prostatic surgery, especially in patients who are intolerant or resistant to quinolones. However, the clinical pharmacokinetics (PK) of the two carbapenems in prostate tissue and attainment of their pharmacodynamic (PD) targets at site of action had been unclear. This study thus examined, for the first time, the clinical PK of doripenem and meropenem in prostate tissue, and estimated their PD target attainment at this site. METHODS: Doripenem (0.25 g or 0.5 g) or meropenem (0.25 g or 0.5 g) was intravenously administered to 101 patients with benign prostatic hypertrophy prior to TURP. Blood samples and prostate tissue samples were collected 0.5, 1, 1.5, 2, 3, 4 and 5 h after starting a 0.5-h infusion. Drug concentrations in plasma and prostate tissue were measured using high-performance liquid chromatography, analyzed using a three-compartment population pharmacokinetic model, and used to estimate the probability of attaining a bactericidal target (40% of the time above the minimum inhibitory concentration [MIC] for bacteria). RESULTS: These carbapenems penetrated similarly into prostate tissue, independently of the dose, with mean prostate tissue/ plasma ratios of 0.166e0.173 (maximum drug concentration) and 0.177e0.187 (area under drug concentration-time curve). Despite this relatively low penetration by doripenem and meropenem, their usual regimens of 0.25 g three times daily and 0.5 g twice daily (0.5-h infusions) achieved a favorable target-attainment probability value of 90.8e95.9%, in prostate tissue, against clinical isolate populations of Escherichia coli and Klebsiella species (the two major causative bacteria in prostatitis). However, Pseudomonas aeruginosa isolate population needed 0.5 g three times daily for probability values of 55.9% for doripenem and 52.3% for meropenem. The prostatic pharmacodynamic-based breakpoint MIC (the highest MIC at which the targetattainment probability in prostate tissue was more than 90%) was 0.063 mg/L for 0.25 g three times daily and 0.125 mg/L for 0.5 g three times daily, for both drugs. CONCLUSIONS: These results define clinical pharmacokinetics of doripenem and meropenem in prostate tissue, while also rationalizing and optimizing their dosing regimens for prostatitis on the basis of site-specific pharmacodynamic target attainment.