Population Pharmacokinetic Modeling and Stochastic Simulations to Support Pediatric Dose Selection of Pimavanserin

Pimavanserin is a selective serotonin-modulating agent with inverse agonist/antagonist activity at the 5-HT2A receptor. Safety and efficacy of pimavanserin 34 mg once daily was studied in adults with hallucinations and delusions associated with Parkinson's disease psychosis and other neuropsychiatric conditions. This analysis used model-based simulations of pimavanserin steady-state exposures to identify a dose that generated pediatric exposures comparable with adult exposures achieved with 34 mg pimavanserin. A population pharmacokinetics model was developed using pooled plasma drug concentration (i.e., actual) data from 13 clinical studies, including a phase 1 study of adolescent pediatric patients (13-17 years) with various psychiatric conditions. Stochastic simulations were performed to predict exposures in a virtual (i.e., simulated) group of pediatric patients (5-17 years). Steady-state measures of area under the plasma concentration-time curve (AUC) and maximum drug concentration (Cmax) were simulated for relevant age and weight stratifications and compared with simulated exposures in adults (18-49 years). Simulated mean AUC ranged 47.41-54.73 ng·d/mL and mean Cmax ranged 41.13-50.07 ng/mL in adults receiving pimavanserin 34 mg. Simulated mean (SD) Cmax with 34 mg pimavanserin was similar in patients aged 10-17 years (56.54 [24.58] ng/mL) and adults. Pimavanserin 20 mg yielded a mean (SD) Cmax most like the 34-mg adult Cmax in patients aged 5-9 years (45.30 [21.31] ng/mL) and in the 14-25 kg pediatric patient weight group (49.18 [22.91] ng/mL). Pimavanserin 20 and 34 mg in pediatric patients aged 5-9 and 10-17 years, respectively, yielded exposures similar to daily pimavanserin 34 mg in adults aged 18-49 years. This article is protected by copyright. All rights reserved.