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 mug/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 T1/2β was observed with the 250 μg/kg dose, and a trend was observed with a greater T1/2β in females at the 1000 μg/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 μg/kg. The pharmacokinetics are independent of dose over this dose range. Copyright (C) 2002 John Wiley & Sons, Ltd.