| Summary: | Peter Dogterom,1 Robert Riesenberg,2 Rik de Greef,1 Justin Dennie,3 Martin Johnson,1 Venkatesh Pilla Reddy,1 André MM Miltenburg,1 Robert L Findling,4 Abhijeet Jakate,5 Timothy J Carrothers,5 Matthew D Troyer3 1Early Stage Development, Merck Sharp and Dohme, Oss, the Netherlands; 2Atlanta Center for Medical Research, Atlanta, GA, 3Merck, Kenilworth, NJ, 4Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD, 5Allergan, Madison, NJ, USA Purpose: This study aimed to characterize the pharmacokinetic (PK) properties, safety, and tolerability of asenapine, and to develop a population PK model in pediatric patients with schizophrenia, bipolar disorder, or other psychiatric disorders. Methods: Two Phase I multiple ascending-dose studies were conducted to evaluate the PK, safety, and tolerability of sublingual asenapine in pediatric patients (age 10–17 years) with schizophrenia or bipolar I disorder. Patients received asenapine 1–10 mg twice daily for up to 12 days. PK parameters (maximum concentration [Cmax], area under the curve from 0 to 12 hours [AUC0–12], time to Cmax [Tmax], and half-life) were summarized for asenapine with descriptive statistics, and safety parameters were collected. A population PK model, which included the two Phase I studies and two additional Phase III efficacy studies (asenapine 2.5–10 mg twice daily for up to 8 weeks, age 10–17 years), was developed using nonlinear mixed-effect modeling based on a previously developed adult PK model. The final model was used in simulations to obtain asenapine-exposure estimates across pediatric subgroups and to determine if intrinsic covariates warrant dose adjustments. Results: The PK of asenapine showed rapid absorption (Tmax ~1 hour) with an apparent terminal half-life between 16 and 32 hours. Increases in mean Cmax and AUC0–12 appeared to be dose-proportional in one study and near dose-proportional in the second study. Steady state was attained within 8 days. The most frequently occurring treatment-emergent adverse events were dysgeusia, sedation, and oral hypoesthesia. Simulation-based estimates of Cmax and AUC0–12 were similar for pediatric and adult patients; age, body-mass index, race, and sex were not associated with changes in asenapine exposure. Conclusion: Asenapine was generally safe and well tolerated in pediatric patients aged 10–17 years. PK and safety data were similar to that observed in the adult population. Intrinsic factors had no significant impact on asenapine exposure, indicating there is no need for dose adjustments in the pediatric population. Keywords: asenapine, pharmacokinetics, schizophrenia, bipolar disorder, child and adolescent, atypical antipsychotic
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