The use of quantitative clinical pharmacology approaches to support moxidectin dosing recommendations in lactation.

Moxidectin is approved by the US Food and Drug Administration (US FDA) for the treatment of onchocerciasis (river-blindness) due to Onchocerca volvulus in patients aged 12 years and older. In onchocerciasis-endemic areas, mass drug administration (MDA) programs with ivermectin, with or without vector control, aim to control the disease, reduce morbidity, interrupt transmission, and more recently, achieve elimination. Moxidectin has the potential to be used in MDA programs. In countries where onchocerciasis is endemic, infants are often breastfed up to the age of 2 years, suggesting that some women are likely to be lactating during such periodic MDA programs. Quantitative analyses of non-clinical and clinical data using non-compartmental analysis and population based pharmacokinetic (popPK) modeling as well as physiologically based pharmacokinetic modeling (PBPK) were performed to determine the amount of moxidectin excreted in breast milk and subsequent exposures in the infant. The results of the analyses were similar. Concentrations of moxidectin in breast milk followed a similar pattern to those in plasma, with maximum concentrations occurring approximately 4 hours after dosing followed by a rapid decline in both breast milk and plasma. As early as two days after dosing, concentrations of moxidectin in breast milk were below the threshold for acceptable daily intake levels established by the European Medicines Agency (EMA) and FDA for secondary exposures from veterinary use, and below the WHO recommended relative infant dose (RID) safety threshold. The analyses were conducted to support prescribers and policy makers on dosing recommendations for moxidectin in lactation.