Population pharmacokinetic modeling to support dose selection of zavegepant nasal spray in pediatrics.
Craig M Comisar (1), Jim Hughes (2), Jose Francis (1), Gary Mo (2), Beikang Ge (3), Rajinder Bhardwaj (1), Mohamed H. Shahin (2), Jing Liu (2)
(1) Certara, USA, (2) Pfizer Inc., USA, (3) Pfizer Pharmaceutical Ltd., China.
Introduction:
Zavegepant nasal spray (ZAVZPRET™, Pfizer) is a calcitonin gene-related peptide receptor antagonist indicated in the United States for acute treatment of migraine in adults, with a recommended dose of 10 mg as needed up to once a day [1].
Objectives:
- To predict zavegepant exposures in pediatric population 6 to 17 years of age and across different body-weight ranges using a zavegepant population pharmacokinetic (PPK) model developed using adult pharmacokinetic (PK) data and assuming empirical allometric scaling.
- To provide dosing selection of zavegepant nasal spray for pediatric population 6 to 17 years of age and across different body-weight ranges by matching pediatric exposures to adult exposures after zavegepant 10 mg nasal spray
Methods:
The PPK model was previously developed and validated using data from 10 phase 1 clinical studies of zavegepant (intravenous, oral, and intranasal formulations) in adults [2]. It is a 3-compartment model with sequential zero- and first-order absorption and first-order elimination from the central compartment. Body weight-based empirical allometric scaling was applied to all disposition parameters using standard exponents (0.75 for clearances and 1 for volumes of distribution). This PPK model was used to simulate zavegepant exposure in virtual pediatric population ≥6 years of age following single administrations of 3 mg, 5 mg, or 10 mg zavegepant nasal spray. For age-based simulations, a representative population of virtual pediatric subjects (n=1000) was generated based on the CDC growth chart describing the age-body weight distribution across pediatrics 6 to 17 years of age [3]. Simulations were also performed across 12 body weight ranges, with 1000 subjects assigned to each range. Predicted exposures (maximum concentration in plasma [Cmax] and area under the curve from 0 to infinity [AUC0-inf]) in the pediatric population following administration of a single dose of 3 mg, 5 mg, and 10 mg zavegepant nasal spray were compared with predicted zavegepant exposures in adults receiving a single dose of 10 mg nasal spray. Ratios of median pediatric exposure to median adult exposure were also calculated. For pediatric dose selection, exposure ratios (for both AUC0-inf and Cmax) between 1 and 2 were considered adequate. Nonlinear mixed-effects modeling software (NONMEM®; version 7.4.3; ICON) and/or R software were used for simulations and analysis.
Results:
Predicted zavegepant exposure in pediatric subjects was between 1- and 2- fold of predicted exposure in adults (receiving a single administration of zavegepant 10 mg nasal spray) at the following doses: 10 mg for adolescents (12 to 17 years of age) and for children 6 to <12 years of age with a body weight >30 kg, and 5 mg for children 6 to <12 years of age with a body weight of >15 to ≤30 kg.
Conclusions:
Based on PPK simulations, zavegepant nasal spray doses selected for pediatrics were 10 mg for adolescents (12 to 17 years of age) and for children 6 to <12 years of age with a body weight >30 kg, and 5 mg for children 6 to <12 years of age with a body weight >15 to ≤30 kg. The pediatric dose selection has been agreed to by the United States Food and Drug Administration for a zavegepant PK study in pediatrics 6 to 12 years of age, and no additional PK data are needed for adolescents.
References:
[1] https://labeling.pfizer.com/ShowLabeling.aspx?id=19471
[2] Pfizer. Data on file.
[3] https://www.cdc.gov/nchs/data/series/sr_11/sr11_246.pdf
[4] Croop R et al. Headache, 62:1153-63, 2022.
