Pharmacokinetic-pharmacodynamic analysis of azithromycin extended release in Japanese patients with common respiratory tract infectious disease

Abstract

Objectives: It is known that the efficacy of azithromycin, in animal infection models, is best correlated with AUC/MIC. The pharmacokinetic-pharmacodynamic (PK-PD) relationship for azithromycin, however, has not been previously confirmed with clinical data. The objectives of this PK-PD analysis were to characterize exposure-response relationships for the efficacy and safety of azithromycin extended release (ER) in Japanese patients, and to evaluate the effects of potential covariates on the prediction of response. Methods: Sparse serum azithromycin concentration, MIC, efficacy and safety data were collected from three Japanese Phase 3 studies of a 2 single dose of azithromycin-ER for respiratory tract infections. These sparse concentration data were combined with data from eight Phase 1 PK studies in Japanese and Western populations, to develop a robust population PK model using a non-linear mixed effects approach. The exposure-response relationships for efficacy and safety were evaluated using logistic regression. Results: A two-compartment model with first-order absorption and first-order elimination with a lag time adequately described the PK of azithromycin-ER, without any significant ethnic differences in AUC. The percentage of bacteriological and clinical success in patients with AUC/MIC> (95.8% and 100%, respectively) was much higher than in those with AUC/MIC≤5 (60.0% and 83.3%, respectively). Conclusions: As expected, the probabilities of success in the clinical and bacteriological responses were positively associated with AUC/MIC, but not with AUC. For the exposure-safety relationship, the incidence of treatment-related diarrhoea was inversely associated with azithromycin exposure. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.