ArticleAntimicrobial agents and chemotherapy2014
Development of a population pharmacokinetic model characterizing the tissue distribution of azithromycin in healthy subjects.
Article in Antimicrobial agents and chemotherapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 4 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed, 4 syntheses or guidelines pooled it, 42 citations in OpenAlex.
- Efficacy and safety of 24 antibiotics for group A streptococcal pharyngitis: a network meta-analysis of 64 randomized controlled trials.Frontiers in public health · 2026Pooled it
- Influential predictors of azithromycin pharmacokinetics: a systematic review of population pharmacokinetics.Annals of medicine · 2025Pooled it
- Significant Predictors of Azithromycin in Population Pharmacokinetic Analysis: A Systematic Review.Drug design, development and therapy · 2025Pooled it
- Pharmacokinetics in Patients with Cystic Fibrosis: A Systematic Review of Data Published Between 1999 and 2019.Clinical pharmacokinetics · 2020Pooled it
- Trial
- Comparison ofMicrobiology spectrum · 2026Article
- Azithromycin Mitigates Experimental Cryptosporidiosis-Driven Ileocecal Adenocarcinoma by Modulating Autophagy, Apoptosis, and PI3K/AKT Signaling.Biomedicines · 2026Article
- Pharmacokinetics of Lekethromycin in Swine Following Intramuscular Administration at Different Doses with a Single Intravenous Reference Dose for Absolute Bioavailability and Matrix Comparison.Veterinary sciences · 2026Article
- Case Commentary: A herculean effort forAntimicrobial agents and chemotherapy · 2025Article
- Plasma concentration of azithromycin and correlation with clinical outcomes in patients with enteric fever.JAC-antimicrobial resistance · 2025Article
- Distribution of Macrolide Resistant Mycoplasma genitalium in Urogenital Tract Specimens From Women Enrolled in a US Clinical Study Cohort.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2023Article
- Tissue Penetration of Antimicrobials in Intensive Care Unit Patients: A Systematic Review-Part II.Antibiotics (Basel, Switzerland) · 2022Review
- Macrolide Treatment Failure due to Drug-Drug Interactions: Real-World Evidence to Evaluate a Pharmacological Hypothesis.Pharmaceutics · 2022Article
- Synergistic Adverse Effects of Azithromycin and Hydroxychloroquine on Human Cardiomyocytes at a Clinically Relevant Treatment Duration.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Model-Informed Drug Development for Anti-Infectives: State of the Art and Future.Clinical pharmacology and therapeutics · 2021Review
- Investigational Treatments for COVID-19 may Increase Ventricular Arrhythmia Risk Through Drug Interactions.CPT: pharmacometrics & systems pharmacology · 2021Article
- Predictions of Systemic, Intracellular, and Lung Concentrations of Azithromycin With Different Dosing Regimens Used in COVID-19 Clinical Trials.CPT: pharmacometrics & systems pharmacology · 2020Article
- Excessive lysosomal ion-trapping of hydroxychloroquine and azithromycin.International journal of antimicrobial agents · 2020Article
- Investigational treatments for COVID-19 may increase ventricular arrhythmia risk through drug interactions.medRxiv : the preprint server for health sciences · 2020Article
- Pharmacokinetics of Macrolide Antibiotics and Transport into the Interstitial Fluid: Comparison among Erythromycin, Clarithromycin, and Azithromycin.Antibiotics (Basel, Switzerland) · 2020Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 MIC90s 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 MIC90s 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.
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