Development of a population pharmacokinetic model to describe azithromycin whole-blood and plasma concentrations over time in healthy subjects

Abstract

Azithromycin (AZI), a broad-spectrum antibiotic, accumulates in polymorphonuclear cells and peripheral blood mononuclear cells. The distribution of AZI in proinflammatory cells may be important to the anti-inflammatory properties. Previous studies have described plasma AZI pharmacokinetics. The objective of this study was to describe the pharmacokinetics of AZI in whole blood (concentration in whole blood [Cb]) and plasma (concentration in plasma [Cp]) of healthy subjects. In this study, 12 subjects received AZI (500 mg once a day for 3 days). AZI Cb and Cp were quantified in serial samples collected up to 3 weeks after the last dose and analyzed using noncompartmental and compartmental methods. After the last dose, Cb was greater than Cp. Importantly, Cb, but not Cp, was quantifiable in all but one subject at 3 weeks. The blood area under the curve during a 24-h dosing interval (AUC24) was ∼2-fold greater than the plasma AUC24, but simulations suggested that Cb was not at steady state by day 3. Upon exploration of numerous models, an empirical 3-compartment model adequately described Cp and Cb, but Cp was somewhat underestimated. Intercompartmental clearance (CL; likely representing cells) was lower than apparent oral CL (18 versus 118 liters/h). Plasma, peripheral, and cell compartmental volumes were 439 liters, 2,980 liters, and 3,084 liters, respectively. Interindividual variability in CL was low (26.2%), while the volume of distribution variability was high (107%). This is the first report to describe AZI Cb in healthy subjects, the distribution parameters between Cp and Cb, and AZI retention in blood for up to 3 weeks following 3 daily doses. The model can be used to predict Cb from Cp for AZI under various dosing regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01026064.).

Figures

Fig 1

AZI blood (□) and plasma (○) concentration-time profiles. Data represent the mean concentration-time profiles in blood and plasma for up to 48 h following the last of the three (500-mg) doses of AZI given once daily.

Fig 2

Diagram of the 3-compartment structural model for AZI concentrations in blood and plasma. ka, absorption rate constant; Tlag, lag time; Cp, plasma concentration; Ct, concentration in peripheral compartment, assumed to be tissue; Cbc, concentration in peripheral compartment, assumed to be blood cells; CLt, intercompartmental clearance to tissue compartment; CLbc, intercompartmental clearance to blood cell compartment; CL, elimination clearance; M, empirical coefficient to blood cell concentration; N, empirical coefficient to plasma concentration.

Fig 3

Goodness-of-fit graphics for blood (left) and plasma (right). Graphs depict the observed concentrations versus the population predictions (A), the observed concentrations versus the individual predictions (B), and the CWRES versus the population predictions (C). The line of identity is included in panels A and B.

Fig 4

Visual predictive check (VPC) in blood (A) and plasma (B). Open circles, observed data points; solid line, predicted 50th percentile; shaded area, area between the predicted 5th and 95th quantiles. Ideally, 90% of the observations should fall inside the 90% prediction interval.

Fig 5

Predictions of AZI accumulation in blood and plasma after long-term (30 days) administration of 500 mg daily. Bold, dashed lines, predicted blood concentration-time profile; thin, solid lines, predicted plasma concentration-time profile.