Population pharmacokinetic analysis of meropenem in Korean patients with acute infections
Dong-Hwan Lee(1,2), Yong-Kyun Kim(3), , Sung-min Kim(3)
(1)Department of Clinical Pharmacology, Pusan National University Hospital, Busan, Korea (2) Bio-Medical Research Institute, Pusan National University Hospital, Busan, Korea (3)Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Korea
Objectives: The aim of this study is to investigate the population pharmacokinetic (PK) profiles of meropenem in Korean patients with acute infections.
Methods: Four consecutive 500-mg or 1000-mg doses of meropenem were intravenously infused over 1 hour every 8 hour for patients with creatinine clearance of ≤ 50 ml/min or > 50 ml/min, respectively. Blood samples from 37 patients at steady-state were taken pre-dose and at 0 min, 30 min and 4-6 hours after the 4th infusion. The population PK analysis was conducted using a nonlinear mixed effect modeling software, NONMEM. Covariate screening was conducted applying general additive models for PK parameters. Likelihood ratio test was used to select significant covariates, with the significance levels of p < 0.05 for selection and p < 0.01 for elimination. The final model was evaluated by the visual predictive check. The probability of patients with T>MIC (the percentage of a dosing interval during which the concentration of drug exceeds the minimal inhibitory concentration) of ≥40% was obtained applying Monte-Carlo simulation with various dose, infusion time, infusion interval and creatinine clearance.
Results: The meropenem PK was well described by a one-compartment model. The typical values (relative standard error) were 0.2657 L/h/kg (12.29%) and 0.4886 L/kg (11.01%) for weight normalized clearance and volume of distribution, respectively. The coefficient of variations of the inter-individual variability (relative standard error) for these parameters were 66.84% (14.37%) and 55.10% (15.06%). Residual variability was best explained by a poisson error model. Doripenem CL was significantly influenced by serum creatinine level (SCR), which explained 11% of the interindividual variability of clearance. The proposed equations to estimate meropenem CL in Korean patients were CL/WT (L/h/kg) = 0.2657 × WT × [SCR / 0.74]-1.017. Most of the observed data were within the 90% prediction interval in the visual predictive check. The simulation shows that the current dosing regimen is less likely to treat patients infected with normal or augmented renal function.
Conclusions: The PK profiles of meropenem at steady-state in Korean patients with acute infections were well described by a one-compartment model. Meropenem clearance was significantly influenced by the serum creatinine level. The dose of meropenem should be adjusted according to MIC.
References:
[1] Li C, Kuti JL, Nightingale CH, Nicolau DP. Population pharmacokinetic analysis and dosing regimen optimization of meropenem in adult patients. J Clin Pharmacol. 2006 Oct;46(10):1171-8
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