Doripenem pharmacokinetics in hemodialysis

Abstract

© Wolters Kluwer Health, Inc. All rights reserved. Background Doripenem is a broad spectrum carbapenem with activity against gram-positive, gram-negative, and anaerobic bacteria. The drug concentration in target sites is an important determinant of carbapenem efficacy. Doripenem is primarily eliminated by kidneys and can be removed by hemodialysis. The purpose of this study was to determine the pharmacokinetics of doripenem in hemodialysis patients with moderate to severe infections. Methods This prospective, single-center study was conducted in end-stage renal disease patients undergoing hemodialysis and receiving doripenem. Low-flux hemodialysis was performed for 4 hours. Blood and dialysate samples were collected during hemodialysis and nonhemodialysis periods. The doripenem concentrations in plasma and dialysate were measured by reverse phase high performance liquid chromatography. The total amount of drug removed during hemodialysis was determined and the hemodialysis clearance of doripenem was calculated using PKSolver, the add-in program for Microsoft Excel. The appropriate dose of doripenem was estimated using Monte Carlo simulation. Results Six patients were eligible for the study. The fraction of doripenem eliminated via hemodialysis was 51.31%. The mean total amount of doripenem removed by 4 hours of hemodialysis was 1472.06 ± 861 mg at a removal rate of 6.13 ± 3.59 mg/min. Hemodialysis drug clearance volume was 26.06 ± 14.59 L/h. The recommended doripenem dose estimated from the simulation was 250 mg infused every 12 hours during hemodialysis and 250 mg infused every 48 hours for nonhemodialysis periods. Conclusions A low-flux dialyzer removes about half of the total amount of doripenem in blood circulation for 4 hours. Therefore, drug dosage adjustment is required for end-stage renal disease patients undergoing hemodialysis.