Date Published: May 14, 2008
Publisher: Public Library of Science
Author(s): Ahmed El-Tahtawy, Paul Glue, Emma N. Andrews, Jack Mardekian, Guy W. Amsden, Charles A. Knirsch, Eric A. Ottesen
Abstract: BackgroundA recent drug interaction study reported that when azithromycin was administered with the combination of ivermectin and albendazole, there were modest increases in 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 FindingsA two-compartment pharmacokinetic model with first-order elimination and absorption was developed. The chosen 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 identified 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.ConclusionsThis 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 was identified (an increase in bioavailability in one subpopulation). Simulations show that the maximum ivermectin 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 of co-administration of azithromycin with the widely used agents ivermectin and albendazole, under field conditions in disease control programs.
Partial Text: The operational efficiency of disease elimination programs in developing countries could be improved by integrating delivery of several interventions at local (village and district) levels –. In areas endemic for co-infection with filarial nematodes and Chlamydia trachomatis, one such integrated disease elimination strategy would be based on mass administration of a three-drug combination: ivermectin for onchocerciasis, albendazole for lymphatic filariasis and azithromycin for trachoma. Regular administration of this combination would also be predicted to reduce other infectious agents including soil transmitted nematodes and bacterial sexually transmitted diseases .
Assessment of the relationship between azithromycin and ivermectin by noncompartmental analysis showed that mean ivermectin AUC and Cmax was increased by 31% and 27%, respectively (see  for complete results). Visual inspection of the magnitude of ivermectin accumulation against azithromycin exposure in the interaction arm showed no obvious relationship (Figure 2), and a very low Pearson’s r2 (0.03).
There are a number of interesting findings from this analysis of data from an interaction study of ivermectin and azithromycin. This is the first published population model of ivermectin pharmacokinetics. It demonstrates the utility of population mixture modeling as an approach to explore drug interactions, especially where there may be population heterogeneity. The mechanism for the interaction was identified (an increase in bioavailability in one subpopulation). The model was used to simulate multiple clinical trials, to identify the maximum exposures that might be observed during co-administration, which permits comparison with previously published safety and pharmacokinetic data.