Director, Clinical Pharmacology Pfizer Inc., Cambridge, MA, USA, United States
Disclosure(s):
Chay Ngee Lim, PhD: No relevant disclosure to display
Objectives: Rimegepant orally disintegrating tablet (ODT) is indicated for acute treatment of migraine (with and without aura) at 75 mg up to once per day and preventive treatment of episodic migraine at 75 mg every other day (EOD) in adults [1]. The objective of this study was to refine rimegepant population pharmacokinetic (PPK) model using adult and pediatric PK data, predict rimegepant exposures, and provide dosing selection, in pediatric populations across different age and body-weight ranges for efficacy and safety studies.
Methods: An established rimegepant PPK model in adults was further developed with the addition of data from 20 pediatric subjects. The PPK model was used to simulate rimegepant exposure in virtual pediatric populations ≥6 years of age following administration of 25, 35, 50, and 75 mg rimegepant ODT given as either a single dose or EOD. For age-based simulations, a representative population of virtual pediatric subjects (n=1000) per 1-year age group was generated based on a CDC growth chart describing age-body weight distribution across children 6 to 17 years of age [2]. Simulations were also performed across body weight ranges in cohorts of 5 kg range increments (n=1000 subjects for each). Predicted exposures in the pediatric population following single (Cmax and AUC0-inf) or EOD (Cmax,ss and AUC0-48h,ss) dosing of 25, 35, 50, and 75 mg rimegepant ODT were compared with predicted exposures in adults following single or EOD dosing of 75 mg rimegepant ODT. Ratios of median exposure (pediatric to adult) close to 1 and not exceeding 2 were required to meet the criteria for pediatric dose selection.
Results: A 2-compartment model with a delayed first-order absorption with 4 transit compartments and optimized allometric scaling of disposition parameters best described rimegepant plasma concentration-time profiles in adults and children. For age-based simulations, the predicted median exposures in adolescents (12 to 17 years of age) following a single dose of 75 mg rimegepant were similar to the predicted exposures in adults receiving the same single dose. Body weight-based simulation in children (6 to < 12 years of age) indicate that a single dose of rimegepant at 75 mg for children with body weight >40 kg, 50 mg for children with body weight >25 kg to ≤40 kg, and 35 mg for children with body weight >15 kg to ≤25 kg would achieve Cmax levels within 0.985-1.74-fold, and AUC0-inf levels within 0.776-1.34-fold of predicted adult levels. Simulations with EOD indicated similar exposure ratios as single dose simulations at same dose levels.
Conclusion: Based on PPK simulations, rimegepant ODT doses (single and EOD) for pediatrics should be 75 mg for adolescents 12 to 17 years of age, 75 mg for children 6 to < 12 years of age with a body weight >40 kg, 50 mg for children 6 to < 12 years of age with a body weight between >25 kg and ≤40 kg, and 35 mg for children 6 to < 12 years of age with a body weight between >15 kg and ≤25 kg.
