Physiologically based pharmacokinetic modeling of daptomycin dose optimization in pediatric patients with renal
Lingling Ye1, Xiang You1, Jie Zhou1
1Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
Insights
Daptomycin dosing for children with kidney problems needs adjustment. Severe impairment significantly increases drug exposure, especially in younger children, requiring careful monitoring.
Area of Science:
- Pharmacology
- Pediatric Nephrology
Background:
- Daptomycin is a crucial antibiotic for Gram-positive infections in both pediatric and adult populations.
- Dosing of daptomycin varies across pediatric age groups.
- Pharmacokinetics of daptomycin in pediatric patients with renal impairment remain unevaluated.
Purpose of the Study:
- To evaluate the pharmacokinetics of daptomycin in pediatric patients with varying degrees of renal impairment.
- To establish and validate a physiologically based pharmacokinetic (PBPK) model for daptomycin in pediatric populations.
Main Methods:
- Development and validation of a PBPK model for daptomycin.
- Simulation of daptomycin disposition in healthy children and children with renal impairment.
- Analysis of daptomycin exposure (Cmax and AUC) across different renal function levels.
Main Results:
- PBPK model simulations demonstrated consistency with observed data (fold error < 2).
- Daptomycin Cmax and AUC were similar in children with mild-to-moderate renal impairment compared to healthy children.
- AUC increased significantly (1.55-fold in severe, 1.85-fold in end-stage renal disease), particularly in younger children, necessitating dose adjustments.
Conclusions:
- Daptomycin dose adjustments are crucial for pediatric patients with renal impairment, especially in severe cases.
- While generally safe, steady-state Cmin may exceed 24.3 mg/L in some instances.
- Weekly creatine phosphokinase monitoring is recommended for children with renal impairment receiving daptomycin.
Abstract:
Background and Objective: Daptomycin is used to treat Gram-positive infections in adults and children and its dosing varies among different age groups. We focused on the pharmacokinetics of daptomycin in children with renal impairment, which has not been evaluated. Methods: A physiologically based pharmacokinetic (PBPK) model of daptomycin was established and validated to simulate its disposition in healthy populations and adults with renal impairment, along with a daptomycin exposure simulated in pediatric patients with renal impairment. Results: The simulated PBPK modeling results for various regimens of intravenously administered daptomycin were consistent with observed data according to the fold error below the threshold of 2. The Cmax and AUC of daptomycin did not differ significantly between children with mild-to-moderate renal impairment and healthy children. The AUC increased by an average of 1.55-fold and 1.85-fold in severe renal impairment and end-stage renal disease, respectively. The changes were more significant in younger children and could reach a more than 2-fold change. This scenario necessitates further daptomycin dose adjustments. Conclusion: Dose adjustments take into account the efficacy and safety of the drug; however, the steady-state Cmin of daptomycin may be above 24.3 mg/L in a few instances. We recommend monitoring creatine phosphokinase more than once a week when using daptomycin in children with renal impairment.
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