The antiparasitic moxidectin: safety, tolerability, and pharmacokinetics in humans.

A study in healthy male volunteers was completed to evaluate the safety, tolerability, and pharmacokinetics of a single oral dose of the antiparasitic moxidectin (MOX). This drug is registered worldwide as a veterinary antiparasitic agent for use in companion and farm animals. This is the first study of MOX in humans. All subjects were between the ages of 18 and 45 years, with normal cardiac, hematologic, hepatic, and renal function. Doses of MOX studied were 3, 9, 18, and 36 mg in cohorts of 6 subjects each (5:1, MOX:placebo). At the 9-mg and 36-mg doses, two separate cohorts were completed, one in the fasted state and one after the consumption of a high-fat breakfast. For all other cohorts, administration was in the fasted state. Safety and tolerability were assessed by physical examinations, ongoing evaluation of adverse events (AEs), and measurement of laboratory values. Pharmacokinetic (PK) samples were collected just prior to dosing and at various time points until 80 days postdose. Safety assessments from all dose groups studied suggested that MOX was generally safe and well tolerated, with a slightly higher incidence of transient, mild, and moderate central nervous system AEs as the dose increased as compared to placebo. The PKs of MOX were dose proportional within the dose range studied, and the elimination half-life (t1/2 elim) was long (mean: 20.2-35.1 days). At the 9-mg and 36-mg doses, a high-fat breakfast was shown to delay and increase the overall absorption but did not increase maximal concentrations when compared to administration in the fasted state. In summary, the results from this study indicate that MOX is safe and well tolerated in humans between the doses of 3 mg and 36 mg.

Pharmacokinetics and dose proportionality of oral moxidectin in beagle dogs.

PURPOSE: To study the pharmacokinetics and dose proportionality of moxidectin in beagle dogs experimentally infected with the filarial parasite Brugia pahangi, and to evaluate and compare the results obtained from population pharmacokinetic analysis and individual compartmental analysis. METHOD: Thirty-six infected dogs were selected and randomly allocated into six treatment groups of six dogs each. Doses of 250 or 1000 microg/kg were given orally. The plasma drug concentration-time data were analyzed by population compartmental and individual compartmental methods. RESULTS: The best pharmacokinetic model was a two-compartment model with first-order absorption. According to the results obtained from population compartmental analysis, moxidectin is a low clearance drug with a relatively high volume of distribution, resulting in a mean terminal half-life of 458 h. Absorption was rapid with a mean absorption half-life of 0.6 h and T(max) of 2.75 h. Significant weight effect was found on Vc. These results were compared with results obtained from individual compartmental approach. A statistically significant (p<0.01) gender difference in T1/2beta was observed with the 250 microg/kg dose, and a trend was observed with a greater T1/2beta in females at the 1000 microg/kg dose. No gender effect on other pharmacokinetic parameters was found. CONCLUSIONS: A pronounced distribution phase was observed and there was a significant weight effect on Vc. Dose proportionality of moxidectin was assessed by comparing the AUC (0-last determination) values for 250 and 1000 microg/kg. The pharmacokinetics are independent of dose over this dose range.