(M-038) Evaluation of Azithromycin Disposition in Pregnant Women Undergoing Cesarean Delivery – A Population-Based PBPK Modeling Approach

Peizhi Li, PharmD – University of Iowa College of Pharmacy; Kenan Gu, PhD – Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases – National Institutes of Health; Geeta Swamy, MD – Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology – Duke University Medical Center; Brenna Hughes, MD, MSCR – Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology – Duke University Medical Center; Guohua An, MD, PhD – University of Iowa College of Pharmacy

Objectives: Cesarean delivery leads to surgical site infections (SSI) in ~5% of cases[1], with higher risks for obese pregnant women[2]. While cefazolin remains the standard prophylactic antibiotic, its coverage is limited. Azithromycin offers broader antimicrobial coverage as an adjunct therapy, but current dosing stems from studies in non-pregnant, normal-weight individuals. The lack of pharmacokinetic (PK) data in pregnant women, especially those with obesity, largely results from challenges in studying this population. This knowledge gap raises concerns about azithromycin dosing efficacy and safety. To address this, an opportunistic clinical PK study was conducted during routine cesarean procedures, providing a rare window to collect valuable plasma and target tissue samples. Subsequently, a population-based physiologically-based pharmacokinetic (PBPK) model was developed to characterize azithromycin PK in this special population.

Methods: A total of 120 pregnant women (50% with obesity) undergoing cesarean delivery due to failed labor received 500 mg iv infusion azithromycin as standard care. The opportunistic design leveraged cesarean procedures to collect blood and normally inaccessible tissue samples. Maternal blood was sampled during surgery and up to 192 hours post-dose, while maternal adipose tissue, myometrium, and fetal cord blood were obtained during surgery. Breast milk samples were collected up to 192 hours.

Given sparse sampling in this vulnerable population, a population PK approach was used. Also, the tissue samples allowed development of a population-based PBPK model that characterizes azithromycin disposition in plasma, adipose, myometrium, and cord blood using nonlinear mixed-effects modeling in NONMEM (7.4.3) with Pirana. Model selection was based on physiological plausibility, parameter stability, diagnostic plots, and objective function value.

Results: The current optimal 8-compartment PBPK model simultaneously describes azithromycin disposition in maternal plasma, adipose tissue, myometrium, and fetal cord blood. This model incorporates pregnancy-related physiological changes, captures the maternal-fetal transfer, and accounts for tissue accumulation via ion trapping. It demonstrates good fit across all samples and accurately characterizes plasma azithromycin concentrations up to 192 hours post-dose. The estimated clearance (58.2 L/h) exceeds values reported in non-pregnant population, reflecting altered drug disposition during pregnancy and obesity. The model successfully characterized tissue concentrations, with adipose-to-plasma and myometrium-to-plasma ratios of 1 and 1.79, respectively.

Conclusions: This study used a population PK approach to gain valuable azithromycin PK insights in pregnant women with cesarean delivery using both plasma and tissue data. Preliminary findings indicate lower azithromycin concentrations in obese-pregnancy groups, suggesting potential dosing adjustments. Ongoing work includes model refinement, followed by Monte Carlo simulations to evaluate probability of target attainment across weight groups, ultimately supporting evidence-based dosing recommendations ensuring efficacy and safety for mother and fetus.

Citations: 1. Farid Mojtahedi M, Sepidarkish M, Almukhtar M, et al. Global incidence of surgical site infections following caesarean section: a systematic review and meta-analysis. J Hosp Infect. 2023;139:82-92. doi:10.1016/j.jhin.2023.05.019
2. Rood KM, Buhimschi IA, Jurcisek JA, et al. Skin Microbiota in Obese Women at Risk for Surgical Site Infection After Cesarean Delivery. Sci Rep. 2018;8(1):8756. Published 2018 Jun 8. doi:10.1038/s41598-018-27134-5

Keywords: PBPK, Pregnancy PK, Antibiotics