Abstract / Summary
Schistosomiasis is an acute and chronic parasitic disease that occurs mainly in sub-Saharan and African countries and for which no treatment is available in preschool-aged children (PSAC). An open-label, Phase III study of arpraziquantel pediatric formulation evaluated safety and efficacy in 280 Schistosoma-infected PSAC (NCT03845140). A population pharmacokinetics (PK) model for arpraziquantel and its active metabolite trans-4-hydroxy-arpraziquantel was developed from concentration measurements (from n = 74 and n = 30 children for arpraziquantel and its metabolite, respectively) after a single dose of 50 or 60 mg/kg arpraziquantel. Extensive PK variability was observed but no significant covariates were identified in the final model other than body weight. Body weight-normalized apparent clearances overlapped across all weight and age categories, supporting body weight-based dosing. No apparent relationship was discernible between an efficacious response and arpraziquantel and/or trans-4-hydroxy-arpraziquantel exposures. Logistic regression analysis indicated higher incidence of treatment-emergent adverse events (TEAEs) with increasing arpraziquantel exposure. For gastrointestinal TEAEs, the incidence was related to infection type with higher incidence in Schistosoma mansoni-infected children. These population PK and exposure-response analyses performed after administration of arpraziquantel pediatric formulation support the weight-based dosing bands posology and the consistency in therapeutic effect over the range of exposures observed in PSAC.