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.

These studies provide evidence of limited glucose lowering and incretin activity for JNJ-38431055 in subjects with T2DM.

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.

The incidence of type 2 diabetes mellitus is increasing worldwide. Several G-protein-coupled receptor agonists are being studied for their efficacy as antidiabetes agents. JNJ-38431055 is a novel, potent, and orally available selective agonist of the glucose-dependent insulinotropic (GPR119) receptor. Double-blind, randomized, placebo-controlled studies were conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of JNJ-38431055 (2.5-800 mg) in healthy male volunteers. The systemic exposure of JNJ-38431055 in plasma increased in proportion to the dose and was not influenced by coadministration of food. The terminal elimination half-life was ~13 h when administered as an oral suspension formulation. JNJ-38431055 was well tolerated and was not associated with hypoglycemia. As compared with placebo, single-dose oral JNJ-38431055 increased postmeal plasma glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) concentrations but did not significantly decrease glucose excursion or increase insulin secretion. However, in a graded glucose infusion study, JNJ-38431055 was shown to induce a higher insulin secretion rate (ISR) relative to placebo at elevated plasma glucose levels. These studies provide evidence for the potential efficacy of JNJ-38431055 as an antidiabetes agent in humans.

Clinical Pharmacology & Therapeutics (2003) 73, P94–P94; doi: