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
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Background
The WHO and onchocerciasis-endemic countries target elimination of the 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 the MDA of moxidectin, an anthelmintic drug for which an 8 mg dose to individuals aged 12 years and older has received regulatory approval. This study was conducted to identify dose levels for children aged 4 to 11 years.
Methods
An open-label, non-comparative, single-dose study in an onchocerciasis-endemic area of Ghana was designed to evaluate moxidectin pharmacokinetics and safety in four groups comprising nine individuals each: those aged 12–17 years, after administration of 8 mg; those aged 8–11 years after administration of 8 mg; those aged 8–11 years after administration of 6 mg; and those aged 4–7 years after administration of 4 mg moxidectin. Evaluations to identify adverse events included physical examination, vital signs, haematology, clinical chemistry and 12-lead electrocardiograms. Moxidectin plasma concentrations were measured at 1, 2, 4, 8, 24 and 72 h and at 1, 2, 4 and 12 weeks post-dose. The maximum concentration (C max ; ng/ml) and area under the concentration–time curve from dosing to infinity (AUC 0-∞ ; ng h/ml) were obtained through non-compartmental analysis.
Results
The 38 adverse events in 24 participants were illnesses typically seen in the study population without treatment (primarily malaria) and were considered not moxidectin-related. The arithmetic mean (± standard deviation) C max and AUC 0-∞ in all groups (range 84.6 ± 18.2 to 118 ± 26.5 ng/ml and 2070 ± 587 to 3910 ± 1070 ng h/ml, respectively) were lower than in those in healthy adults administered 36 mg moxidectin (range 252 ± 50.3 to 296 ± 47 ng/ml and 10835 ± 2587 to 14972 ± 2233 ng h/ml, respectively), the highest and well-tolerated dose given to humans. Mean C max and AUC 0-∞ in groups 1–3 (range 84.6 ± 18.2 to 118 ± 26.5 ng/ml and 2920 ± 2120 to 3910 ± 1070 ng h/ml, respectively) exceeded those in O. volvulus -infected adults administered 8 mg (63.1 ± 20.0 ng/ml and 2738 ± 1606 ng h/ml, respectively). In group 4, mean C max (89.4 ± 24.1 ng/ml) exceeded that in O. volvulus -infected adults administered 8 mg moxidectin (63.1 ± 20.0 ng/ml). Mean AUC 0-∞ (2070 ± 587 ng h/ml) exceeded that in O. volvulus -infected adults administered 4 mg moxidectin (1169 ± 488 ng h/ml), 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 children aged between 8 and 11 years and 4 mg for children aged between 4 and 7 years were selected for further single-dose studies.
