Pharmacokinetics, safety, and biologic effects of azithromycin in extremely preterm infants at risk for ureaplasma colonization and bronchopulmonary dysplasia

Abstract

Ureaplasma spp. respiratory tract colonization is a significant risk factor for bronchopulmonary dysplasia (BPD), a chronic lung disorder in preterm infants. As an initial step preparatory to future clinical trials to evaluate the clinical efficacy of azithromycin to prevent BPD, the authors characterized the pharmacokinetics, safety, and biological effects of a single intravenous dose of azithromycin (10 mg/kg) in preterm neonates (n = 12) 24 to 28 weeks gestation at risk for Ureaplasma infection and BPD. A 2-compartment structural model with the clearance and volume of peripheral compartment (V2) allometrically scaled on body weight (WT) best described the pharmacokinetics of azithromycin in preterm neonates. The estimated parameters were clearance [0.18 L/h × WT(kg)(0.75)], intercompartmental clearance [1.0 L/h], volume of distribution of central compartment [0.93 L], and V2 [14.2 L × WT(kg)]. There were no serious adverse events attributed to azithromycin. A single dose of azithromycin did not suppress inflammatory cytokines or myeloperoxidase activity in tracheal aspirates. These results demonstrated the safety of azithromycin and developed a pharmacokinetic model that is useful for future simulation-based clinical trials for eradicating Ureaplasma and preventing BPD in preterm neonates.

Conflict of interest statement

Conflict of Interest/Disclosure

The authors declare no conflict of interest that may interfere with data interpretation. Dr. Ahmed Othman was an employee of University of Maryland at the time of the design and initiation of the study and is currently an employee of Abbott Laboratories.

Figures

Figure 1

Diagnostic scatter plots for the population PK model. (A) population-predicted versus observed azithromycin plasma concentrations; (B) individual-predicted versus observed azithromycin (AZI) plasma concentrations; (C) weighted residuals versus population predicted plasma concentrations; and (D) weighted residuals versus time (The solid lines represent the lines of identity in A and B and zero weighted residuals in C and D).

Figure 2

Observed (closed circles) and the post-hoc predicted (solid lines) azithromycin plasma concentrations versus time profiles for each neonate.

Figure 3

Azithromycin i.v. simulated plasma concentration versus time profiles in preterm neonates after the following dosage regimens (A) 10 mg/kg/day × 3 days, n=1000, and (B) 20 mg/kg/day × 3 days, n=1000. Median plasma concentrations and 90% prediction interval (calculated from the 5th and 95th percentiles of the simulated concentrations) are depicted in the figure. The dotted lines represent the MIC50 (1 µg/mL) and MIC90 (4 µg/mL) of azithromycin against Ureaplasma.