Pharmacokinetics of Transfer of Azithromycin into the Breast Milk of African Mothers

Abstract

Azithromycin (AZI) is used for its antibiotic and antimalarial properties in pregnancy. Reported estimates of AZI breast milk transfer, based on concentrations in mostly single samples from small numbers of women, have suggested that infant intake is safe. To better characterize infant intake and the associated potential benefits and risks, AZI was measured by liquid chromatography-mass spectrometry in four breast milk samples taken over 28 days postpartum from each of 20 Gambian women given 2 g AZI during labor. A population pharmacokinetic model utilizing published parameters for AZI disposition in pregnancy, the present breast milk concentrations, and increasing/decreasing sigmoid maximum-effect (Emax) functions adequately described temporal changes in the milk/plasma ratio. The median estimated absolute and relative cumulative infant doses were 4.5 mg/kg of body weight (95% prediction interval, 0.6 to 7.0 mg/kg) and 15.7% (95% prediction interval, 2.0 to 27.8%) of the maternal dose, respectively; the latter exceeded the recommended 10% safety limit. Although some infants with bacterial infections may benefit from AZI in breast milk, there is a risk of hypertrophic pyloric stenosis with a worst-case number needed to harm of 60 based on the present and available epidemiologic data. (This study has been registered at ClinicalTrials.gov under registration no. NCT01800942.).

FIG 1

(Top) Population average maternal plasma azithromycin concentration, based on a previously published study (5) (line), together with breast milk azithromycin concentrations from the 20 women given 2 g during labor in the present study (○). (Bottom) The log₁₀(milk/plasma ratio) for azithromycin calculated using median parameters from a previously published study (5) (○) and combined model for changes in the milk/plasma ratio over time (black line), together with the effects of the positive and negative sigmoid E_max relationships for the milk/plasma ratio (gray lines).

FIG 2

Goodness-of-fit plots for azithromycin in breast milk. (A and B) Observed breast milk concentration plotted against population (A) and individual (B) predicted breast milk concentrations. (C and D) Weighted residuals against time from first dose (C) and time from birth (D).

FIG 3

Prediction-corrected visual predictive check for azithromycin in breast milk. Observed 50th (solid line) and 10th and 90th (dashed lines) percentiles are shown within their simulated 95% CIs (gray shaded areas) with overlying data points (○).

FIG 4

Simulation results demonstrating the median (solid black lines), maximum (dashed black lines), and 95% prediction intervals (gray-shaded areas) for absolute (in milligrams per kilogram) and percent relative total infant doses (A and C) and absolute (in milligrams per kilogram per day) and percent relative daily infant doses (B and D) from time of dose for 2 g Stat (A and B) and 1 g daily over 3 days (C and D). The cross-hatched areas during the first 3 days represent the lack of data during this period.

FIG 5

Additional cases of infantile hypertrophic pyloric stenosis (left y axis) estimated based on simulations performed for a 2-g Stat maternal dose during labor (solid black line) and 1 g daily for 3 days (dashed black line), assuming a threshold effect for the cumulative dose over the first 14 days of life. The corresponding numbers needed to harm (gray lines) are presented on the right y axis.