Optimal regimens of praziquantel for schistosomiasis in young children

ABSTRACT Praziquantel (PZQ) is the drug of choice for control and treatment of schistosomiasis. Pharmacokinetic (PK) data for establishing a safe and effective PZQ dose in preschool-aged children are limited. We characterized PZQ pharmacokinetics in children aged 1–4 years with intestinal schistosomiasis. PZQ was administered at either 40 mg/kg or 80 mg/kg (split into two doses of 40 mg/kg, 3 h apart), and plasma concentrations were quantified. These data were pooled with pre-existing PK data from children aged 3–8 years, who received PZQ 40 mg/kg or 60 mg/kg. A population PK model was fitted to the pooled data, and individual drug exposure was estimated. Pharmacodynamic outcomes were egg reduction rate, and both parasitological and antigenic cure at 4 weeks post-treatment. The relationship between PZQ exposure and cure was established using regression analysis. Monte Carlo simulations were performed to assess the adequacy of weight-based PZQ dosing. A two-compartment model, with first-order absorption and elimination, best described PZQ disposition. Total body weight was allowed to influence clearance and the central compartment volume, with fixed allometric exponents 0.75 and 1, respectively. Simulations indicated that both weight-banded fixed-dose regimens and individual weight-based dosing achieved comparable drug exposures. The area under the concentration-time curve (AUC 0–24 ) of the total drug was a strong predictor of parasitological cure. PZQ 80 mg/kg achieved parasitological cure rates >85% but may still be insufficient for complete worm elimination, as demonstrated by the lower rate (69.5%) of antigen clearance. Further optimization of anti-schistosomiasis treatments may be required to achieve complete worm elimination in mass treatment programs. IMPORTANCE Schistosomiasis is a neglected tropical disease of significant global health concern, disproportionately affecting children in endemic areas. Praziquantel (PZQ) is the only drug currently recommended by the WHO, as a single 40 mg/kg dose for treatment of schistosomiasis. However, pharmacokinetic-pharmacodynamic (PK/PD) data to support optimal dosing of PZQ for children <5 years are limited. In this study, we evaluated the PK/PD of PZQ, administered at 80 mg/kg (split into two doses of 40 mg/kg, 3 h apart), vs the standard 40 mg/kg regimen, in children aged 1–4 years. Our results indicate that PZQ exposure following 80 mg/kg achieves parasitological cure more effectively than the current standard 40 mg/kg single-dose regimen. In children with a heavy infection intensity, the 80 mg/kg dose may still be insufficient to achieve complete worm clearance. These results highlight the need for further optimization of PZQ regimens and the discovery and development of new antiparasitic agents.