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

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 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.

Pharmacokinetics of a single 1g dose of azithromycin in rectal tissue in men

“…While no data exist on azithromycin levels in rectal mucus, azithromycin has been reported in cervical mucus [11] and gastric mucus [13] so it remains plausible that drug would be present in rectal mucus. Thirdly, high tissue concentrations may not always translate to clinical efficacy due to the relative distribution of azithromycin between different tissue compartments, [39] particularly under the influences of pH [40, 41] and that intracellular concentrations may be potentially unavailable for activity. [41] However despite these pharmacokinetic limitations, observational studies have reported an efficacy of 83% for 1g azithromycin for treating rectal infections [5], supporting the likelihood that reasonable rectal tissue concentrations are being obtained following a 1g dose with the results of this study representing the only published study to date that has quantified rectal concentrations against treatment efficacy.…”

Transport of Azithromycin into Extravascular Space in Rats

“…However, most studies have focused on the AZM concentration in WBCs, different tissue-specific phagocytes (i.e., the intracellular tissue space), and tissue homogenates (8,(11)(12)(13). The AZM concentration in tissue homogenates represents a mixture of AZM concentrations in the intracellular and extracellular tissue spaces; estimation of drug concentrations in the infection site is not possible.…”

Pharmacokinetic considerations regarding the treatment of bacterial sexually transmitted infections with azithromycin: a review

“…The key pharmacokinetic parameters for antimicrobials commonly used for treatment of STIs are summarized in Table 1. 25,26 Protein binding for azithromycin is particularly interesting as unlike most other antimicrobials, protein binding among healthy individuals is dosedependent, decreasing from 51% at 0.02 µg/mL to 7% at 2 µg/mL, 19 which suggests at high concentrations, protein binding will become saturated resulting in more free drug.…”

“…73 One reason for azithromycin's long intracellular half-life is that after it enters the acidic intracellular compartments the drug is trapped within the cell (ion trapping). 26 While ion trapping helps to concentrate the drug intracellular at the site of infection, it does prevent the drug from diffusing back into the plasma. As a result, concerns remain about the presence of low concentrations in extracellular compartments where organisms may replicate, 74 and where prolonged exposures to sub-inhibitory concentrations could induce or select azithromycin resistance.…”

“…75 We do not know what intracellular drug levels exert induction or selection pressure for resistance in different bacterial species. 26,73,76 As the MIC of azithromycin for MG is lower (0.002-0.008 mg/L) than that for NG (0.5 mg/L), it is likely that such an effect would be present for longer in-vivo with MG compared with NG. 77,78 MG develops resistance very easily when using azithromycin monotherapy because it requires mutation of only one gene allele encoding the azithromycin target 23S rRNA.…”