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 34 mg 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 34 mg pimavanserin. A population pharmacokinetics model was developed using pooled plasma drug concentration (ie, actual) data from 13 clinical studies, including a phase 1 study of adolescent pediatric patients (aged 13-17 years) with various psychiatric conditions. Stochastic simulations were performed to predict exposures in a virtual (ie, simulated) group of pediatric patients (aged 5-17 years). 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 18-49 years). The simulated mean AUC ranged from 47.41 to 54.73 ng d/mL and the mean Cmax ranged from 41.13 to 50.07 ng/mL in adults receiving pimavanserin 34 mg. The simulated mean (SD) Cmax of 56.54 (24.58) ng/mL with pimavanserin 34 mg in patients aged 10-17 years was similar to that in adults. Pimavanserin 20 mg yielded a mean (SD) Cmax of 45.30 (21.31) ng/mL in patients aged 5-9 years and 49.18 (22.91) ng/mL in the pediatric patient weight group of 14-25 kg, which are values close to the Cmax in adults treated with 34 mg. 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.