Population pharmacokinetics of intravenous colistin in pediatrics (poppicop study)

Abstract

Background: Colistin use in pediatrics is surging in line with the increase of multidrug-resistant Gram-negative bacteria (MDR-GNB). However, the appropriate dose is uncertain owing to the lack of pharmacokinetics data. In this study, we aimed to characterize the pharmacokinetic parameters of colistin in pediatric patients, identify the factors influencing the pharmacokinetic parameters, and propose optimal dosage regimens. Methods: A prospective, multicenter, population pharmacokinetic (PPK) study was conducted. Serial blood samples were obtained from patients after receiving the standard colistin recommended dose of 5 mg of colistin base activity (CBA)/kg/day. Plasma colistin concentrations were measured. Data were pooled from this study and the previous study to create a data set for PPK analysis. A PPK model was performed with the PhoenixTM 64 version 8.3. The final model was evaluated by goodness-of-fit plots, bootstrap analysis, and prediction corrected-visual predictive check. Simulation using the final PPK model was done to propose optimal colistin dosage regimens. Results: From March 2018 to February 2021, 59 patients (187 plasma samples) were enrolled. Data were pooled with 20 patients (147 plasma samples) from the previous study. A total of 334 plasma colistin concentrations from 79 pediatric patients with a median age (IQR) of 2.6 years (0.8-6.8) were adequately described by a one-compartment model with first-order elimination along with serum creatinine (SCr) as a significant covariate on colistin clearance (CL). Colistin CL was 0.069 L/h*kg, the volume of distribution (V) was 0.658 L/kg. Model-based simulation demonstrated that with the recommended dose of 5 mg of CBA/kg/day, the probability target attainment (PTA) was 18.2-30.1% and 40.2-63.0% in the patients with a SCr level of 0.1-0.3 mg/dL and 0.31-0.75 mg/dL, respectively when the target plasma colistin average steady-state concentration (Css,avg) was 2 mg/L. For a lower target Css,avg of 1 mg/L, PTA was 61.1–75.0% and 82.6–93.6% in the patients with a SCr level of 0.1-0.3 mg/dL and 0.31-0.75 mg/dL, respectively. Conclusions: SCr is a significant covariate on colistin clearance in pediatric patients. Patients with a lower SCr level require a higher dose of colistin, especially higher than the current recommendation, owing to the increase of colistin elimination.