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A reappraisal of polymyxin B dosing based on population pharmacokinetic model in patient with renal insufficiency

By Xuben Yu, Chunhong Zhang, Jingye Pan, Ying Dai, Ziye Zhou, Fan Yang, Ruolan Sun, Yexuan Wang, Yancheng Cao, Changcheng Sheng, Zheng Jiao, Guanyang Lin

Posted 28 Jan 2020
medRxiv DOI: 10.1101/2020.01.24.20018481

BackgroundCurrent FDA-approved label recommends polymyxin B dosing should be adjusted according to renal function, despite several studies proved poor correlation between polymyxin B PK and creatinine clearance. The study aims to assess the impact of renal function on polymyxin B metabolism and identify an alternate dosing strategy by population analysis. MethodsBlood samples from adult patients were collected at steady state during routine therapeutic drug monitoring. Nonlinear mixed effects modeling was employed to build a population PK model of polymyxin B. Monte Carlo simulations were performed to design polymyxin B dosing regimens across various renal function. ResultsPharmacokinetic analyses included 112 polymyxin B concentrations at steady state from 32 adult patients aged 37-93 received intravenous polymyxin B (100-200 mg/d). The creatinine clearance in patients was 5.91-244 mL/min. In the final population PK model, CrCL was the significant covariate on CL (typical value, 1.59 L/hr; between-subject variability, 13%). Mean (SD) individual empirical Bayesian estimates of CL was 1.75 (0.43) L/hr. A new dosing strategy combining the PK/PD targets and Monte Carlo simulation indicated that polymyxin B dose reductions improved the probability of achieving optimal exposures in simulated patients with renal insufficiency. For severe infections caused by organisms with MIC of [≥] 2 mg/L, though a high daily dose (e.g. 200mg/day) would possible for bacterial eradication, the risk of nephrotoxicity is significantly increased. ConclusionA population PK model was established to develop individualized polymyxin B dosage regimens that the dose of polymyxin B should be adjusted according to CrCL.

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