An Extrapolation Approach to Aprepitant Pediatric Drug Development
Anne Chain (1), Leila Kheibarshekan (2), Rebecca Wrishko (3), Nathalie H Gosselin (2)
(1) MSD, New Jersey, USA (2) Certara, Montreal, Canada, (3) MSD, Pennsylvania, USA
Objectives: 1- Identify an appropriate 1-day intravenous (IV) dose of fosaprepitant in pediatric subjects that provides exposures similar to those associated with efficacy in adults. 2- Identify a 3-day combined IV/oral fosaprepitant and aprepitant regimen that provides exposures similar to the approved pediatric 3-day oral regimen of aprepitant.
Methods: A population PK model of fosaprepitant and aprepitant was developed using 4 completed studies with different formulations (capsule, powder for suspension, IV) and various dose amounts and regimens (3-day oral, 3-day IV and oral, 1-day IV) in 316 pediatric subjects aged 6 months to 17 years old. Monte-Carlo simulations were performed using the final model to simulate exposure profiles of aprepitant to support 1-day and 3-day dosing regimens of fosaprepitant and aprepitant in pediatric subjects. Model fidelity was assessed using goodness-of-fit plots and VPCs. Individual PK parameters were computed using a non-compartmental analysis approach on simulated rich concentration-time profiles. Simulated 1-day IV exposures were compared with target exposures corresponding to the 1-day IV fosaprepitant regimen approved in adults. The simulated 3-day IV/oral exposures were compared with target exposures corresponding to the approved three-day oral regimens in pediatric population.
Results: The final model was a two-compartment model with first-order absorption, lag-time and bioavailability. Allometric factors were included in all systemic parameters. Age, dose and formulation were identified as covariates in the model. Based on exposure levels observed in adults after a single IV dose of fosaprepitant, a regimen of 5 mg/kg and 4 mg/kg were appropriate for subjects 6 months to <2 years old and 2 to 12 years old, respectively. Regimens of 115 mg on Day 1 and 80 mg on Days 2 and 3 in adolescents as well as 3 mg/kg on Day 1 and 2 mg/kg on Days 2 and 3 in subjects < 12 years old were adequate for a 3-day IV /oral regimen.
Conclusions: Appropriate 1-day IV doses of fosaprepitant were identified for pediatric subjects. These results supported an extrapolation approach in the 1-day IV setting using model-based evaluations to ascertain a dosing recommendation, which facilitated the early termination of a Phase 3 trial. In addition, a successful bridging strategy was also used to find 3-day IV/oral regimen for use in children.