PI-114 - POPULATION PHARMACOKINETIC ANALYSIS TO OPTIMIZE THE DOSING REGIMEN OF 17-OHPC FOR PREVENTION OF PRETERM BIRTH

P. Dodeja¹, M. Gopalakrishnan², S. Sharma³, W. Zhao⁴, S. Caritis⁵, R. Venkataramanan¹; ¹University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA, ²University of Maryland, Baltimore, Baltimore, MD, USA, ³AstraZeneca, South San Francisco, CA, USA, ⁴University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA, ⁵Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Background: Preterm birth ( < 37 weeks of gestation) is the leading cause of infant mortality globally [1]. 17-hydroxyprogesterone caproate (17-OHPC), a hydroxyprogesterone analog, administered at a fixed intramuscular (I.M) dose of 250 mg weekly, is used off-label for the prevention of recurrent preterm birth [2]. We have shown that 250 mg dose results in highly variable drug exposure and may be inadequate for most women to prevent preterm birth [3,4]. We aimed to develop a population pharmacokinetic (PopPK) model for 17-OHPC in pregnant women to optimize dosing based on patient covariates.

Methods: Pooled plasma concentration-time data for 17-OHPC given 250 or 500 mg I.M weekly from 521 women (1534 concentration-time data points) from five multi center, prospective clinical studies in pregnant women with singleton or multifetal gestation (16 3/7 to 22 6/7 weeks gestation) were analyzed. The curated data included longitudinal records of clinical (progesterone, hydroxyprogesterone levels, pro-inflammatory cytokines, gestational age at enrollment, sampling and delivery) and demographic (body weight, body mass index, race and age) characteristics . PopPK model development and verification was performed using nonlinear mixed effect modeling in Pumas v2.5.1.

Results: A one-compartment model with a sequential first and zero-order absorption model adequately described the data. Our model estimated that 25% of the I.M dose is absorbed through a first order process, whereas the remaining 75% dose is absorbed via a zero-order process after a lag time of 2 days. Similar to singleton gestation PK [4], the typical estimate for apparent clearance (CL/F) was 2,488 L/day and apparent volume (V/F) was 26,392 L with an inter-individual variability (IIV) ranging between 36-78%. Inclusion of maternal body weight as a covariate explained the variability on 17-OHPC CL/F and V/F.

Conclusion: A comprehensive PopPK model for 17-OHPC in pregnant women from multiple clinical studies was developed. The PopPK model will be utilized to perform exposure–response (gestational age at delivery) analysis to inform 17-OHPC dosing recommendations for pregnant women.

1. Manuck TA et al. doi: 10.1016/j.ajog.2016.01.004.
2. Baxter C et al. doi: 10.1016/j.ajog.2023.07.042
3. Caritis et al. doi: 10.1016/j.ajog.2024.04.020.
4. Sharma et al. doi:10.1111/bcp.12990