Population Pharmacokinetic Analysis of Doripenem after Intravenous Infusion in Korean Patients with Acute Infections

Abstract

We investigated the population pharmacokinetics (PK) of doripenem in Korean patients with acute infections and determined an appropriate dosing regimen using a Monte Carlo simulation for predicting pharmacodynamics (PD). Patients (n ϭ 37) with a creatinine clearance (CL CR ) of 20 to 50 ml/min or Ͼ50 ml/min who received a 250-mg or 500-mg dose of doripenem over the course of 1 h every 8 h, respectively, were included in this study. Blood samples were taken predosing and 0 h, 0.5 h, and 4 to 6 h after the fourth infusion. A nonlinear mixed-effect modeling tool was used for the PK analysis and pharmacodynamic simulation; doripenem PK were well described by a one-compartment model. The population mean values of the body weight (WT)-normalized clearance (CL/WT) and the body weight-normalized volume of distribution (V/WT) were 0.109 liter/h/kg of body weight (relative standard error, 9.197%) and 0.280 liter/kg (relative standard error, 9.56%), respectively. Doripenem CL was significantly influenced by CL CR . The proposed equation to estimate doripenem CL in Korean patients was CL/WT ϭ 0.109 ϫ WT ϫ (CL CR /57) 0.688 , where CL/WT is in liters per hour per kilogram. CL in Korean patients was expected to be lower than that in Caucasian patients, regardless of renal function. The Monte Carlo simulation showed that 90% attainment of target PK/PD magnitudes could be achieved with the usual dosing regimens when the MIC was Յ1 mg/liter. However, prolonged infusions (4 h) should be considered, especially when patients have augmented renal function and for patients infected with pathogens with a high MIC. Our results provide an individualized doripenem dosing regimen for patients with various renal functions and for patients infected with bacteria with decreased susceptibility.

Pharmacokinetics of Doripenem in Healthy Koreans and Monte Carlo Simulations to Explore Optimal Dosage Regimens in Patients With Normal and Enhanced Renal Function

“…Various PK/PD studies have shown that dosage regimen adjustments are necessary not only for patients with renal impairment but also for patients with normal or augmented renal clearance. 17 , 23 – 29 We expected that PD predictions based on an adequate understanding of doripenem PK will enhance efficacy without increasing side effects, and we conducted the first clinical study to investigate doripenem PK in healthy Korean volunteers. In this study, we explored the efficacy in various situations, including various dosage regimens and MICs, by applying Monte Carlo simulations with the final PK parameters.…”

“…Moreover, patients with an augmented renal clearance (CL CR > 130 mL/min) in intensive care units should be treated with 4-hour infusions to reach a PTA above 90%. 17 …”

Impact of High Body Weight on Mortality in Critically Ill Patients Receiving Meropenem for Pneumonia

“…However, body size and composition characteristics affect most PK parameters and have a large impact on drug metabolism and distribution [9]. In patients with larger body size, both volume of distribution (Vd) and clearance (Cl) of carbapenems are increased, due to the higher lean body weight, increased plasma volume, and elevated glomerular filtration rate [10]. The increased Vd and Cl can lead to a substantially lower serum concentrations of carbapenems in those patients [11].…”

Population pharmacokinetic analysis of doripenem for Japanese patients in intensive care unit

“…The full model incorporated Ccr in CL body , Alb in CL CRRT , and BW in V 1 . Ccr and BW have been selected as covariates in previous reports 7,8,11,26 , and Alb has been reported to be removed by continuous hemofiltration using a cellulose triacetate membrane 27 . Next, at the backward elimination step, when Ccr was excluded from the full model (model #8), OFV increased significantly ( Table 2).…”