Modeling and Simulation Analysis of Aprepitant Pharmacokinetics in Pediatric Patients With Postoperative or Chemotherapy-Induced Nausea and Vomiting

Abstract

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.

A simple extemporaneous oral suspension of aprepitant yields sufficient pharmacokinetic exposure in children

“…In line with the published model of Chain et al, 8 maturation was tested as covariate on CL, but this did not improve our model. In addition, no trend for an age effect was found looking at (ETA) plots.…”

“…This is also in accordance with previous literature. 8,20 However, both previous studies used lag-time to correct for the delayed absorption, which represents an abrupt increase in the absorption rate from a value of zero. From a physiological approach, one would expect a rather slow increase starting from time point zero.…”

“…Furthermore, age, as measure of maturation, was evaluated as covariate on clearance (CL), because Chain et al found this to be a significant covariate on CL. 8…”

Chemotherapy-induced nausea and vomiting in children – the missing evidence

“…The dosing schedules result in comparable systemic exposures as seen in adults, but with lower CINV control than reported in adult trials. 15,18 The use of aprepitant and fosaprepitant is limited by their properties as moderate CYP3A4 inhibitors, and they have the potential to increase the AUC of CYP3A4 sensitive substrates, including many antineoplastic agents, by up to five-fold. 3 A systematic review identified clinically significant pharmacokinetic interactions between aprepitant/ fosaprepitant and the antineoplastic agents bosutinib, cabazitaxel, and cyclophosphamide and adverse events when aprepitant/ fosaprepitant was co-administered with ifosfamide.…”

“…Recommendations on doses are complicated by lack of paediatric pharmacokinetic studies, and children's doses cannot always be extrapolated from adult studies. 14,15,18 Optimal acute CINV control is the most crucial factor to prevent anticipatory and delayed CINV, 8 but effective antiemetic strategies must be available to manage CINV in these phases too. POGO has developed guidelines for breakthrough, refractory, and anticipatory CINV in children, but the recommendations within these guidelines are generally weak.…”