Development of a Population Pharmacokinetic Model Characterizing the Tissue Distribution of Azithromycin in Healthy Subjects

• Published in: Antimicrobial agents and chemotherapy Vol. 58; no. 11; pp. 6675 - 6684
• Main Authors: Zheng, Songmao, Matzneller, Peter, Zeitlinger, Markus, Schmidt, Stephan
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.11.2014
• Subjects: Adult; Anti-Bacterial Agents; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - therapeutic use; Azithromycin; Azithromycin - blood; Azithromycin - pharmacokinetics; Azithromycin - therapeutic use; Drug Resistance, Bacterial; Half-Life; Healthy Volunteers; Humans; Male; Microbial Sensitivity Tests; Pharmacology; Respiratory Tract Infections - drug therapy; Respiratory Tract Infections - microbiology
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/AAC.02904-14

Recent clinical trials indicate that the use of azithromycin is associated with the emergence of macrolide resistance. The objective of our study was to simultaneously characterize free target site concentrations and correlate them with the MIC 90 s of clinically relevant pathogens. Azithromycin (500 mg once daily [QD]) was administered orally to 6 healthy male volunteers for 3 days. The free concentrations in the interstitial space fluid (ISF) of muscle and subcutaneous fat tissue as well as the total concentrations in plasma and polymorphonuclear leukocytes (PMLs) were determined on days 1, 3, 5, and 10. All concentrations were modeled simultaneously in NONMEM 7.2 using a tissue distribution model that accounts for nonlinear protein binding and ionization state at physiological pH. The model performance and parameter estimates were evaluated via goodness-of-fit plots and nonparametric bootstrap analysis. The model we developed described the concentrations at all sampling sites reasonably well and showed that the overall pharmacokinetics of azithromycin is driven by the release of the drug from acidic cell/tissue compartments. The model-predicted unionized azithromycin (AZM) concentrations in the cytosol of PMLs (6.0 ± 1.2 ng/ml) were comparable to the measured ISF concentrations in the muscle (8.7 ± 2.9 ng/ml) and subcutis (4.1 ± 2.4 ng/ml) on day 10, whereas the total PML concentrations were >1,000-fold higher (14,217 ± 2,810 ng/ml). The total plasma and free ISF concentrations were insufficient to exceed the MIC 90 s of the skin pathogens at all times. Our results indicate that the slow release of azithromycin from low pH tissue/cell compartments is responsible for the long terminal half-life of the drug and thus the extended period of time during which free concentrations reside at subinhibitory concentrations.