The combination of polymyxins, meropenem, and sulbactam shows efficacy against multi-drug-resistant Acinetobacter baumannii, commonly infecting blood, skin, lung, and heart muscle.
This study aimed to predict drug disposition and efficacy in these tissues using physiologically based pharmacokinetic (PBPK) modeling, linking drug exposures to pharmacodynamic indices against A. baumannii.
An adult PBPK model was developed for the three antibiotics and scaled to pediatrics, accounting for renal and non-renal clearances. Model reliability was assessed by comparing simulations to observed data. Pharmacodynamic indices evaluated whether adult and pediatric dosing provided sufficient coverage.
Modeled plasma drug exposures aligned with literature data. Mean fold errors were within a reasonable range for meropenem (0.710-1.37), colistin (0.981-1.47), and sulbactam (0.647-1.39). Simulated tissue exposures were consistent with reported penetration rates. In a virtual pediatric population (2–<18 years), target pharmacodynamic indices were achieved in 85–90% of subjects after administering pediatric dosing regimens (meropenem 30 mg/kg, sulbactam 40 mg/kg three times daily, colistin 5 mg/kg/day).
The PBPK modeling supports pediatric dosing regimens of meropenem/colistin/sulbactam for co-administration against A. baumannii infections in blood, lung, skin, and heart tissues.
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.
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