The effect of azithromycin on ivermectin pharmacokinetics - A population pharmacokinetic model analysis

Abstract

Background: A recent drug interaction study reported that when azithromycin was administered with the combination of ivermectin and alendazole, there was modest increasesin ivermectin pharmacokinetic parameters. Data from this study were reanalyzed to further explore this observation. A compartmental model was developed and 1,000 interaction studies were simulated to explore extreme high ivermectin values that might occur. Methods and Findings: A two-compartment pharmacokinetic model with first-order elimination and absorption was developed. The chsen final model had 7 fixed-effect parameters and 8 random-effect parameters. Because some of the modeling parameters and their variances were not distributed normally, a second mixture model was developed to further explore these data. The mixture model had two additional fixed parameters and idntified two populations, A (55% of subjects), where there was no change in bioavailability, and B (45% of subjects), where ivermectin bioavailability was increased 37%. Simulations of the data using both models were similar, and showed that the highest ivermectin concentrations fell in the range of 115-201 ng/mL. Conclusions: This is the first pharmacokinetic model of ivermectin. It demonstrates the utility of two modeling approaches to explore drug interactions, especially where there may be population heterogeneity. The mechanism for the interaction exposures that might be observed during co-administration with azithromycin are below those previously shown to be safe and well tolerated. These analyses support further study and co-administration of azithromycin with the widely used agents ivermectin and albendazole, under field conditions in disease control programs.© 2008 El-Tahtawy et al.