Prediction of Tissue Exposures of Meropenem, Colistin, and Sulbactam in Pediatrics Using Physiologically Based Pharmacokinetic Modeling

Background The combination of polymyxins, meropenem, and sulbactam demonstrated efficacy against multi-drug-resistant bacillus Acinetobacter baumannii. These three antibiotics are commonly used against major blood, skin, lung, and heart muscle infections. Objective The objective of this study was to predict drug disposition and extrapolate the efficacy in these tissues using a physiologically based pharmacokinetic modeling approach that linked drug exposures to their target pharmacodynamic indices associated with antimicrobial activities against A. baumannii. Methods An adult physiologically based pharmacokinetic model was developed for meropenem, colistin, and sulbactam and scaled to pediatrics accounting for both renal and non-renal clearances. The model reliability was evaluated by comparing simulated plasma and tissue drug exposures to observed data. Target pharmacodynamic indices were used to evaluate whether pediatric and adult dosing regimens provided sufficient coverage. Results The modeled plasma drug exposures in adults and pediatric patients were consistent with reported literature data. The mean fold errors for meropenem, colistin, and sulbactam were in the range of 0.710-1.37, 0.981-1.47, and 0.647-1.39, respectively. Simulated exposures in the blood, skin, lung, and heart were consistent with reported penetration rates. In a virtual pediatric population aged from 2 to < 18 years, the interpretive breakpoints were achieved in 85-90% of subjects for their targeted pharmacodynamic indices after administration of pediatric dosing regimens consisting of 30 mg/kg of meropenem, and 40 mg/kg of sulbactam three times daily as a 3-h or continuous infusion and 5 mg/kg/day of colistin base activity. Conclusions The physiologically based pharmacokinetic modeling supports pediatric dosing regimens of meropenem/colistin/sulbactam in a co-administration setting against infections in the blood, lung, skin, and heart tissues due to A. baumannii.