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

Abstract

Pimavanserin is a selective serotonin-modulating agent with inverse agonist/antagonist activity at the 5-hydroxytryptamine2A (5-HT2A ) receptor. The safety and efficacy of pimavanserin 34mg once daily were 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 34mg pimavanserin. A population pharmacokinetics model was developed using pooled plasma drug concentration (ie, actual) data from 13 clinical studies, including a phase1 study of adolescent pediatric patients (aged 13-17years) with various psychiatric conditions. Stochastic simulations were performed to predict exposures in a virtual (ie, simulated) group of pediatric patients (aged 5-17years). Steady-state measures of the 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 (aged 18-49years). The simulated mean AUC ranged from 47.41 to 54.73ng d/mL and the mean Cmax ranged from 41.13 to 50.07ng/mL in adults receiving pimavanserin 34mg. The simulated mean (SD) Cmax of 56.54(24.58)ng/mL with pimavanserin 34mg in patients aged 10-17years was similar to that in adults. Pimavanserin 20mg yielded a mean (SD) Cmax of 45.30(21.31)ng/mL in patients aged 5-9years and 49.18(22.91)ng/mL in the pediatric patient weight group of 14-25kg, which are values close to the Cmax in adults treated with 34mg. Pimavanserin 20 and 34mg in pediatric patients aged 5-9 and 10-17years, respectively, yielded exposures similar to daily pimavanserin 34mg in adults aged 18-49years.