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. 2014 Mar 5;3(3):e103.
doi: 10.1038/psp.2013.80.

Population pharmacokinetics of azithromycin in whole blood, peripheral blood mononuclear cells, and polymorphonuclear cells in healthy adults

Affiliations

Population pharmacokinetics of azithromycin in whole blood, peripheral blood mononuclear cells, and polymorphonuclear cells in healthy adults

M R Sampson et al. CPT Pharmacometrics Syst Pharmacol. .

Abstract

Azithromycin's extensive distribution to proinflammatory cells, including peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs), may be important to its antimicrobial and anti-inflammatory properties. The need to simultaneously predict azithromycin concentrations in whole blood ("blood"), PBMCs, and PMNs motivated this investigation. A single-dose study in 20 healthy adults was conducted, and nonlinear mixed effects modeling was used to simultaneously describe azithromycin concentrations in blood, PBMCs, and PMNs (simultaneous PK model). Data were well described by a four-compartment mamillary model. Apparent central clearance and volume of distribution estimates were 67.3 l/hour and 336 l (interindividual variability of 114 and 122%, respectively). Bootstrapping and visual predictive checks showed adequate model performance. Azithromycin concentrations in blood, PBMCs, and PMNs from external studies of healthy adults and cystic fibrosis patients were within the 5th and 95th percentiles of model simulations. This novel empirical model can be used to predict azithromycin concentrations in blood, PBMCs, and PMNs with different dosing regimens.

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Figures

Figure 1
Figure 1
Azithroycin mean (±SE) (a,b) and individual (c,d) concentration–time profiles for all timepoints (a,c) and for the first 24-h period (b,d). Dashed line, 250-mg dose group; solid line, 1,000-mg dose group; green, whole blood; red, peripheral blood mononuclear cells; blue, polymorphonuclear cells.
Figure 2
Figure 2
Four-compartment mamillary structural model. Comp1, central compartment; Comp2, peripheral blood mononuclear cell compartment; Comp3, polymorphonuclear cell compartment; and Comp4, tissue compartment. Azithromycin concentrations in whole blood are equal to A*[Comp1] + B*[Comp2] + C*[Comp3], where the coefficients A and B were estimated empirically, and C was fixed. CL12, 13, 14, and 41 are intercompartmental clearances; CL1–3 are elimination clearances.
Figure 3
Figure 3
(a) population predicted and (b) individual predicted vs. observed azithromycin concentrations. Green circles, whole blood; red diamonds, peripheral blood mononuclear cells; blue triangles, polymorphonuclear cells.
Figure 4
Figure 4
Conditional weighted residuals vs. (a) population predictions (PRED) and (b–d) time. Green circles, whole blood; red diamonds, peripheral blood mononuclear cells; blue triangles, polymorphonuclear cells; dashed line, lowess trend line.
Figure 5
Figure 5
Visual predictive checks. Markers, observed data; shaded area, 90% prediction interval; solid lines, median of observed data; dashed lines, median of simulated data; green circles, whole blood; red diamonds, peripheral blood mononuclear cells; blue triangles, polymorphonuclear cells.
Figure 6
Figure 6
Comparison of model predictions to external data. Azithromycin concentrations in (a) peripheral blood mononuclear cells (PBMCs) and (b) polymorphonuclear cells (PMNs) of healthy individuals after receiving 500 mg of azithromycin daily for 3 days. Small solid markers with error bars, reported azithromycin PBMC concentrations in 24 healthy volunteers (mean ± SD); large open markers without error bars, reported mean azithromycin concentrations in 12 healthy volunteers; red diamonds, PBMCs; blue triangles, PMNs; solid lines represent the 5th, 50th, and 95th percentiles of model-simulated (n = 5,000) concentrations. (c) Cmax and (d) Cmin of azithromycin concentrations in PMNs in cystic fibrosis (CF) patients after receiving 500 mg of azithromycin daily for 35 days. Open blue triangles, reported azithromycin PMN concentrations in eight CF patients (mean ± SD); solid lines represent the 5th, 50th, and 95th percentiles of model-simulated (n = 5,000) concentrations.

References

    1. United States Food and Drug Administration Azithromycin label; 2011.
    1. Shinkai M., Henke M.O., Rubin B.K. Macrolide antibiotics as immunomodulatory medications: proposed mechanisms of action. Pharmacol. Ther. 2008;117:393–405. - PubMed
    1. Piacentini G.L., et al. Azithromycin reduces bronchial hyperresponsiveness and neutrophilic airway inflammation in asthmatic children: a preliminary report. Allergy Asthma Proc. 2007;28:194–198. - PubMed
    1. Vos R., et al. A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation. Eur. Respir. J. 2011;37:164–172. - PubMed
    1. Culic O., Erakovic V., Parnham M.J. Anti-inflammatory effects of macrolide antibiotics. Eur. J. Pharmacol. 2001;429:209–229. - PubMed

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