Pharmacokinetics of oral moxidectin in individuals with Onchocerca volvulus infection

BackgroundOnchocerciasis ("river blindness"), is a neglected tropical disease caused by the filarial nematode Onchocerca volvulus and transmitted to humans through repeated bites by infective blackflies of the genus Simulium. Moxidectin was approved by the United States Food and Drug Administration in 2018 for the treatment of onchocerciasis in people at least 12 years of age. The pharmacokinetics of orally administered moxidectin in 18- to 60-year-old men and women infected with Onchocerca volvulus were investigated in a single-center, ivermectin-controlled, double-blind, randomized, single-ascending-dose, ascending severity of infection study in Ghana. Methodology/Principal findingsParticipants were randomized to either a single dose of 2, 4 or 8 mg moxidectin or ivermectin. Pharmacokinetic samples were collected prior to dosing and at intervals up to 12 months post-dose from 33 and 34 individuals treated with 2 and 4 mg moxidectin, respectively and up to 18 months post-dose from 31 individuals treated with 8 mg moxidectin. Moxidectin plasma concentrations were determined using high-performance liquid chromatography with fluorescence detection. Moxidectin plasma AUC(0-infinity) (2 mg: 26.7-31.7 days*ng/mL, 4 mg: 39.1-60.0 days*ng/mL, 8 mg: 99.5-129.0 days*ng/mL) and C-max (2mg, 16.2 to17.3 ng/mL, 4 mg: 33.4 to 35.0 ng/mL, 8 mg: 55.7 to 74.4 ng/mL) were dose-proportional and independent of severity of infection. Maximum plasma concentrations were achieved 3 to 4 hours after drug administration. The mean terminal half-lives of moxidectin were 20.6, 17.7, and 23.3 days at the 2, 4 and 8 mg dose levels, respectively. Conclusion/SignificanceWe found no relationship between severity of infection (mild, moderate or severe) and exposure parameters (AUC(0-infinity) and C-max), T-1/2 and T-max for moxidectin. T-max, volume of distribution (V/F) and oral clearance (CL/F) are similar to those in healthy volunteers from Europe. From a pharmacokinetic perspective, moxidectin is an attractive long-acting therapeutic option for the treatment of human onchocerciasis. Author summaryThe 2017 Global Burden of Disease Study estimated 20.9 million individuals with onchocerciasis, primarily in Africa. Onchocercal vision impairment/blindness and skin disease (e.g., skin pigment loss, debilitating itching) impact the social and economic life of infected individuals and their communities. This motivates onchocerciasis elimination efforts, today primarily through annual or biannual ivermectin treatment of affected communities. Despite progress towards elimination in many areas, others are not progressing well towards elimination and may require alternative treatment strategies. Moxidectin, approved by the United States Food and Drug Administration in 2018 for treatment of onchocerciasis in people at least 12 years old, could be an alternative. How the amount of a drug in the body changes over time is important for choosing a dose and treatment regimen and for regulatory approval. We measured moxidectin blood levels in 18 to 60 year old men and women with onchocerciasis. We found that moxidectin blood levels peaked around three-four hours after ingestion, that moxidectin stayed in the body for a long time (i.e., its elimination half-life was around 20 days) and that moxidectin blood levels depended on the dose, but not the infection severity as measured by the number of onchocerciasis parasites in the skin.