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A population pharmacokinetic (pop PK) model of polymyxin B was developed using nonlinear mixed‐effects (NONMEM) modeling based on free plasma concentrations to determine whether dose adjustment is required in critically ill patients. One thousand pharmacokinetic profiles for virtual patients with a body weight of 70 kg were simulated using Monte Carlo simulation at different dose scenarios, and area under the concentration–time curve of free drug (fAUC) was computed. The probability of target attainment (PTA) at each minimum inhibitory concentration (MIC) was calculated using fAUC/MIC as a pharmacokinetic/pharmacodynamic (PK/PD) index. The final population PK model was a 2‐compartment model. PTA showed that 3.5 mg/kg/day regimens of polymyxin B effectively achieved the fAUC/MIC target of 10 (one log10 kill) against Pseudomonas aeruginosa strains with MIC of 1 mg/L or less (PTA, 90.7% or greater), while the dose regimen were ineffective against strains with an MIC of 2 mg/L or greater (PTA, 56.9% or less). For Klebsiella pneumoniae, the fAUC/MIC target of 17.4 (one log10 kill) was achieved in more than 90.4% of cases for MIC of 0.5 mg/L or less with 3 mg/kg/day regimens. However, the PTA decreased dramatically as MICs increased above 1 mg/L (PTA, 56.1% or less). The polymyxin B dosage regimen of 3.5 mg/kg/day and 3 mg/kg/day are sufficient to treat P. aeruginosa infections with an MIC of 1 mg/L or less and K. pneumoniae infections with an MIC of 0.5 mg/L or less, respectively. The current recommended dose (1.5–3 mg/kg/day) of polymyxin B appears inadequate to attain the PK/PD target for therapeutic efficacy against infections caused by P. aeruginosa and K. pneumoniae isolates when MIC is above the values. [ABSTRACT FROM AUTHOR]

Busulfan is a bifunctional alkylating agent that is widely used before hematopoietic stem cell transplantation (HSCT), in combination with other chemotherapeutic drugs. As of 2020, there is no population pharmacokinetic (popPK) model for busulfan in Chinese pediatric patients. A systemic external evaluation of 11 published popPK models was conducted in Chinese pediatric patients undergoing HSCT. Forty pediatric patients were enrolled in this study, with a total of 183 blood concentrations. The relative prediction error (PE%), median PE%, median absolute PE%, and percentage of PE% within ±20% and ±30% were calculated in prediction‐based diagnostics. Simulation‐based diagnostics were conducted through a prediction‐ and variability‐corrected visual predictive check and the normalized prediction distribution error. The relative individual prediction error was calculated using Bayesian forecasting with 1 to 3 concentration points. The 1‐compartment open linear popPK model, which was built by Su‐jin Rhee et al (model H), incorporating the patient's body surface area, age, dosing day, and aspartate aminotransferase as significant covariates had preferable predictability than other popPK models. In prediction‐based diagnostics, the median PE%, percentage of PE% within ±20%, and percentage of PE% within ±30% of model H were 8.48%, 45.35%, and 59.56%, respectively. The normalized prediction distribution error of model H showed that it followed the normal distribution. Based on Bayesian forecasting, model H showed good predictive performance. Thus, model H was the most appropriate model that can be used clinically for individualized dosage adjustments in Chinese pediatric HSCT patients. [ABSTRACT FROM AUTHOR]