Identification of a moxidectin dose for 4- to 11-year-old children to support registration and potential use for onchocerciasis elimination: Results of an open-label pharmacokinetic and safety study in an onchocerciasis endemic area in Ghana

Background: WHO and endemic countries target elimination of transmission of Onchocerca volvulus, the parasite causing onchocerciasis, primarily through ivermectin mass drug administration (MDA). In Africa, alternative treatment strategies are required to achieve or accelerate elimination. One of these is MDA of moxidectin, for which an 8 mg dose from age 12 years onward has received regulatory approval. This study was conducted to identify dose levels for 4-11-year-old children. Methods: An open-label, non-comparative, single-dose study in an onchocerciasis-endemic area of Ghana evaluated moxidectin pharmacokinetics and safety in four groups of nine individuals: (1) aged 12-17 years after 8 mg, (2) 8-11 years after 8 mg, (3) 8-11 years after 6 mg and (4) 4-7 years after 4 mg moxidectin. Evaluations to identify adverse events included physical examination, vital signs, haematology, clinical chemistry and 12-lead ECGs. Moxidectin plasma concentrations were measured 1, 2, 4, 8, 24 and 72 hours, and 1, 2, 4, and 12 weeks post-dose. The maximum concentration (Cmax) and area under the concentration-time curve from dosing to infinity (AUC0-∞) were obtained through non-compartmental analysis. Results: The 38 adverse events in 24 participants reflected events typically seen in the study population without treatment and were considered not moxidectin-related. Arithmetic mean (± standard deviation) Cmax (ng/mL) and AUC0-∞ (ng • h/mL) in all groups (range 84.6±18.2 to 39 118±26.5 and 2070±587 to 3910±1070, respectively) were lower than in healthy adults administered 36 mg (range 252±50.3 to 296±47 and 10835±2587 to 14972±2233, respectively), the highest and well-tolerated dose given to humans. Mean Cmax and AUC0-∞ in groups 1-3 (range 84.6±18.2 to 118±26.5 and 2920±2120 to 3910±1070, respectively) exceeded those in O. volvulus infected adults administered 8 mg (63.1±20.0 and 2738±1606, respectively). In group 4, mean Cmax (89.4±24.1) exceeded that in O. volvulus infected adults administered 8 mg (63.1±20.0). Mean AUC0-∞ (2070±587) exceeded that in O. volvulus infected adults administered 4 mg (1169±488), a dose shown to be almost as efficacious as 8 mg. Conclusions: Considering the safety data, exposures and potential MDA operational aspects, 8 mg for 8-11-year- and 4 mg for 4-7-year-old children were selected for further single-dose studies.