Population pharmacokinetics of selexipag for dose selection and confirmation in pediatric patients with pulmonary arterial hypertension.

Abstract

Selexipag is an oral selective prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension (PAH) in adults. To date, no treatment targeting the prostacyclin pathway is approved for pediatric patients. Our goal is to identify a pediatric dose regimen that results in comparable exposures to selexipag and its active metabolite JNJ-68006861 as those shown to be efficacious in adult PAH patients. Extrapolation from the population pharmacokinetic (PK) model developed in adults (GRIPHON study; NCT01106014) resulted in the definition of three different pediatric body weight groups (≥9 to <25 kg, ≥25 to <50 kg, and ≥50 kg) with corresponding starting doses (100, 150, and 200 μg twice daily) and maximum allowed doses (800, 1200, and 1600 μg twice daily). The proposed pediatric dose regimen was subsequently tested in a clinical study (NCT03492177), including 63 pediatric PAH patients ≥2 to <18 years of age and a body weight range of 9.9-93.5 kg. The body weight-adjusted dose regimen for selexipag resulted in comparable systemic exposures to selexipag and its active metabolite in pediatric patients as previously observed in adult PAH patients. Updating the adult selexipag population PK model provided overall consistent parameters and confirmed that the PK characteristics of selexipag and its active metabolite were comparable between pediatric and adult patients. The presented selexipag dose regimen for pediatric PAH patients is considered appropriate for continuing the clinical evaluation of the safety and efficacy of selexipag in pediatric patients ≥2 years of age.