Modeling and Simulation Analysis of Aprepitant Pharmacokinetics in Pediatric Patients With Postoperative or Chemotherapy-Induced Nausea and Vomiting.
| Autor: | Chain A, Wrishko R, Vasilinin G, Mouksassi S |
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| Jazyk: | angličtina |
| Zdroj: | The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG [J Pediatr Pharmacol Ther] 2020; Vol. 25 (6), pp. 528-539. |
| DOI: | 10.5863/1551-6776-25.6.528 |
| Abstrakt: | Objectives: Aprepitant is effective for the prevention of chemotherapy-induced or postoperative nausea and vomiting (CINV/PONV). The aim of this study was to develop a population pharmacokinetic (PK) model of aprepitant in pediatric patients and to support dosing recommendations for oral aprepitant in pediatric patients at risk of CINV. Methods: A population PK model was constructed based on data from 3 clinical studies in which children (6 months to 12 years) and adolescents (12-19 years) were treated with a 3-day regimen of oral aprepitant (capsules or suspension), with or without intravenous fosaprepitant on day 1 (CINV), or a single dose of oral aprepitant (capsules or suspension; PONV). Nonlinear mixed-effects modeling was used for model development, and a stepwise covariate search determined factors influencing PK parameters. Simulations were performed to guide final dosing strategies of aprepitant in pediatric patients. Results: The analysis included 1326 aprepitant plasma concentrations from 147 patients. Aprepitant PK was described by a 2-compartment model with linear elimination and first-order absorption, with allometric scaling for central and peripheral clearance and volume using body weight, and a cytochrome P450 3A4 maturation component for the effect of ontogeny on systemic clearance. Simulations established that application of a weight-based (for those <12 years) and fixed-dose (for those 12-17 years) dosing regimen results in comparable exposures to those observed in adults. Conclusions: The developed population PK model adequately described aprepitant PK across a broad pediatric population, justifying fixed (adult) dosing for adolescents and weight-based dosing of oral aprepitant for children. Competing Interests: Disclosure Anne Chain and Rebecca Wrishko are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and hold stock in the company. Grygoriy Vasilinin is an employee of Certara Inc, Montreal, Quebec, and a paid consultant for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Samer Mouksassi is an employee of Certara Inc, Montreal, Quebec, and a paid consultant for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. ClinicalTrials.gov identifiers: NCT00080444, NCT00818259, NCT00819039 (Copyright Pediatric Pharmacy Association. All rights reserved. For permissions, email: mhelms@pediatricpharmacy.org 2020.) |
| Databáze: | MEDLINE |
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