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

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Abstract

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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Authors and Affiliations

  1. School of Medicine and Pharmacy, Ocean University of China, Qingdao, People’s Republic of China

    Shixing Zhu, Jiayuan Zhang, Zhihua Lv & Mingming Yu

  2. Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, People’s Republic of China

    Zhihua Lv & Mingming Yu

  3. Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA

    Peijuan Zhu

  4. SunLife Biopharma, Morris Plains, NJ, USA

    Charles Oo

  5. Department of Statistics, State University of Maringá, Maringá, Paraná, Brazil

    Sherwin K. B. Sy

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  1. Shixing Zhu
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Correspondence to Mingming Yu or Sherwin K. B. Sy.

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This work was supported by a grant from Shandong Provincial Natural Science Foundation (ZR2019BC025).

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CO is the owner of SunLife Biopharma, which is a private consulting firm. All other authors have nothing to disclose.

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Zhu, S., Zhang, J., Lv, Z. et al. Prediction of Tissue Exposures of Meropenem, Colistin, and Sulbactam in Pediatrics Using Physiologically Based Pharmacokinetic Modeling. Clin Pharmacokinet 61, 1427–1441 (2022). https://doi.org/10.1007/s40262-022-01161-y

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  • DOI: https://doi.org/10.1007/s40262-022-01161-y

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