Dosage adjustment for ceftazidime in pediatric patients with renal impairment using physiologically based pharmacokinetic modeling
J Zhou, X You, M Ke, L Ye, W Wu, P Huang… - Journal of pharmaceutical …, 2021 - Elsevier
J Zhou, X You, M Ke, L Ye, W Wu, P Huang, C Lin
Journal of pharmaceutical sciences, 2021•ElsevierPhysiologically based pharmacokinetic (PBPK) modeling has unique advantages in
investigating the pharmacokinetics of drugs in special populations. Our aim is to design
optimized dosing regimens for ceftazidime in renally-impaired pediatric patients using PBPK
modeling. Models for healthy and renally-impaired adults were developed, verified, and
adapted for children to predict ceftazidime exposure in pediatric patients with varying
degrees of renal impairment, capturing age-and weight-related pharmacokinetic changes …
investigating the pharmacokinetics of drugs in special populations. Our aim is to design
optimized dosing regimens for ceftazidime in renally-impaired pediatric patients using PBPK
modeling. Models for healthy and renally-impaired adults were developed, verified, and
adapted for children to predict ceftazidime exposure in pediatric patients with varying
degrees of renal impairment, capturing age-and weight-related pharmacokinetic changes …
Abstract
Physiologically based pharmacokinetic (PBPK) modeling has unique advantages in investigating the pharmacokinetics of drugs in special populations. Our aim is to design optimized dosing regimens for ceftazidime in renally-impaired pediatric patients using PBPK modeling. Models for healthy and renally-impaired adults were developed, verified, and adapted for children to predict ceftazidime exposure in pediatric patients with varying degrees of renal impairment, capturing age- and weight-related pharmacokinetic changes. We derived a dosage-adjusted regimen for renally-impaired children based on pharmacokinetic data and evaluated the pharmacodynamics of ceftazidime. The PBPK models adequately predicted ceftazidime exposures in populations after single- and multi-dose administrations, with fold error values within 1.1 between simulated and observed data. In moderate, severe, and end-stage renally-impaired pediatric patients, the areas under the plasma concentration-time curves (AUCs) were 1.87-fold, 3.56-fold, and 6.19-fold higher, respectively, than in healthy children when treated with the same dose of 50 mg/kg. Pharmacodynamic verification indicated that the recommended doses of 28, 15, and 8 mg/kg administered three times daily (every 8 h) to pediatric patients with moderate, severe, and end-stage renal disease, respectively, were sufficient to attain the target of maintaining the free plasma concentration at or above minimum inhibitory concentration (MIC) during 70% of the dosing interval (70% fT > MIC: nearly 100% target attainment for susceptible MIC of 4 mg/L and >70% for intermediate MIC of 8 mg/L). Our PBPK model can be an effective tool to support dosing recommendations in pediatric patients with different degrees of renal impairment.
Elsevier
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