Excretion of Moxidectin into Breast Milk and Pharmacokinetics in Healthy Lactating Women

Abstract

Moxidectin is a macrocyclic lactone drug derived from the actinomycete Streptomyces cyanogriseus and is currently being used as a veterinary product for the prevention of canine heartworm disease and for the treatment of internal and external parasites in cattle, sheep, goats, and horses. It is being developed by the World Health Organization (WHO) as a potential macrofilaricidal agent for mass drug administration for the elimination of onchocerciasis (river blindness) in humans caused by the parasitic worm Onchocerca volvulus. Ivermectin (Stromectol; Merck & Co., Inc.) is currently used in mass drug administration programs, but an alternative agent would potentially offer a choice in treatment. Mass drug administration is a process that would call for administration of single doses of medicine, under the supervision of a community health worker, to an entire community at one time.Knowing the extent of excretion of moxidectin into breast milk and the pharmacokinetics of the drug in lactating women will help the community health worker make appropriate decisions about dosing, hence the need for this study. Preclinical studies have shown that the absolute bioavailability of moxidectin is variable, ranging from 19% in rats to 90% in dogs (9). After oral administration, moxidectin is quickly absorbed, with the time to peak plasma concentration (t max ) being 3.7 Ϯ 1.5 h in 27 fasting healthy volunteers receiving an 8-mg dose. Administration of moxidectin with food has been shown to increase the mean peak plasma concentration (C max ) and total area under the concentration-time curve (AUC) by 34% and 39%, respectively (8).The apparent volume of distribution (V z /F) of moxidectin is large (2,000 to 3,500 liters), and moxidectin has a low clearance (CL) (2.37 to 3.50 liters/h) and undergoes very slow elimination, with the terminal-phase elimination half-life (t 1/2 ) being 485 to 842 h (4).A study in lactating dairy sheep showed that after administration of a single oral dose of 200 g/kg of body weight of moxidectin, 2.1% Ϯ 0.33% of the administered dose was excreted in milk for more than 35 days after dosing (7). The ratio of the total AUC curve for moxidectin in breast milk (AUC milk ) to the AUC was 14.3 Ϯ 1.88, indicating that although the total amount of drug that entered the breast milk was small, moxidectin preferentially entered breast milk compared to results for plasma. Similar results were seen in a study in goats (1), where 5.7% Ϯ 1.0% of an orally administered dose of 0.2

Effect of moxidectin on CYP3A4 activity as evaluated by oral midazolam pharmacokinetics in healthy subjects

“…7,15 Administration of single oral midazolam doses 7 and 89 days after moxidectin administration does not appear to affect moxidectin PK parameters. Current treatment of onchocerciasis involves single doses of ivermectin administered annually by community health workers throughout infected areas.…”

Evaluation of the Cardiac Safety of Long‐Acting Endectocide Moxidectin in a Randomized Concentration‐QT Study

“…No identifiable pro-arrhythmic risk was identified through routine electrocardiogram (ECG) safety assessment of 1,105 patients with onchocerciasis and 244 healthy volunteers who received single oral doses of moxidectin up to 36 mg in phase I to III clinical trials. 6,7,[9][10][11][12][13] Onchocerciasis is endemic in the most remote and resource-poor settings of sub-Saharan Africa and treatment with ivermectin is currently through mass drug administration programs involving whole communities (excluding young children and pregnant women) with limited medical supervision or follow-up. Moxidectin is likely to have a similar usage, providing a rationale for conducting a definitive human QT prolongation risk-assessment to confirm earlier findings.…”

“…An in vivo cardiovascular safety pharmacology study showed no adverse effects (AEs) of moxidectin on the cardiovascular system in the dog at up to 1 mg/kg 6 . No identifiable pro‐arrhythmic risk was identified through routine electrocardiogram (ECG) safety assessment of 1,105 patients with onchocerciasis and 244 healthy volunteers who received single oral doses of moxidectin up to 36 mg in phase I to III clinical trials …”

Research for new drugs for elimination of onchocerciasis in Africa

“…Research into moxidectin’s potential to have a higher effect on O. volvulus viability and/or fertility than ivermectin was initiated by WHO/TDR in the late 1990’s (Tagboto and Townson, 1996). Five Phase 1 studies in healthy volunteers were conducted (Cotreau et al., 2003, Korth-Bradley et al., 2011, Korth-Bradley et al., 2012, Korth-Bradley et al., 2013, Korth-Bradley et al., 2014). A Phase 2 study in Ghana determined whether moxidectin was safe enough in O. volvulus infected people to be evaluated in a Phase 3 study and obtained initial efficacy data (Awadzi et al., 2014).…”