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

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Abstract
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. Sparse serum azithromycin concentration, MIC, efficacy and safety data were collected from three Japanese Phase 3 studies of a 2 g 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. 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 > 5 (95.8% and 100%, respectively) was much higher than in those with AUC/MIC ≤ 5 (60.0% and 83.3%, respectively). 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.

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