(W-111) Pharmacokinetics of Long-Acting Naltrexone in Pregnancy: Insights from Physiologically Based Pharmacokinetic Modeling

Ahizechukwu Eke, MD PhD MPH – Associate Professor of Maternal Fetal Medicine, Gynecology & Obstetrics, Johns Hopkins University School of Medicine; Mathangi Gopalakrishnan, MPharm, PhD – Assistant Professor, Pharmacy Practice, University of Maryland School of Pharmacy

Standard medication-assisted treatments for opioid use disorder, like methadone or buprenorphine, pose risks in pregnancy, including maternal overdose and neonatal withdrawal syndrome. Naltrexone is a well-tolerated alternative that blocks opioid effects, aiding full recovery. However, its use in pregnant subjects is limited due to the mandatory 7-10 days of opioid abstinence before initiation and daily oral dosing adherence issues. Although a long-acting injectable (LAI) formulation of naltrexone has improved adherence and a study showed that supervised withdrawal maintains clinical benefits¹, more data are needed for its full adoption in pregnancy. To address this, we aim to use a physiologically based pharmacokinetic (PBPK) modeling approach to describe LAI naltrexone pharmacokinetics in pregnancy for the first time.

The physiological processes and ordinary differential equations governing drug disposition in our PBPK model have been described previously². Naltrexone’s physicochemical properties were used to predict drug partitioning into various tissues using the Rodgers and Rowland method in the base adult intravenous (IV) model. After validating the IV model with observed data, formulation-specific parameters for intramuscular (IM) absorption were integrated to establish an adult IM model of LAI naltrexone. Following successful validation, the model was extended to pregnancy by integrating pregnancy-induced physiological changes, a fetoplacental compartment, and inclusion of myometrium and placenta as additional eliminating organ. Maternal plasma naltrexone profiles were simulated for 100 non-pregnant virtual females, both at pre-conception and during pregnancy, at the approved dose of 380 mg. Fetal naltrexone concentrations were assessed throughout pregnancy, and comparisons were made between simulated pre-conception and pregnancy, as well as maternal and fetal pharmacokinetic profiles.

The base and IM PBPK models were validated with predictions within 1 – 2 absolute average folds of the observed data. Key systemic parameters affected by pregnancy, such as organ weights, blood flows, and hematocrit levels, were compared with available data due to the lack of PK data for LAI naltrexone in pregnancy. The simulated virtual females, with a mean (standard deviation) age and body weight of 23.1 (5) years and 61.1 (8.9) kg, had a mean C_max, AUC_0-7days and AUC_0-28days of 29.4 ng/ml, 142 ng⋅d/ml, and 148 ng⋅d/ml, respectively. Maternal overall exposure (AUC_0-28days) increased 1.4, 1.4 and 1.7 times during the first, second and third trimester of pregnancy. Although fetal Cmax was 50% lower than maternal C_max, the overall fetal exposure (AUC_0-28days) was comparable (0.97 – 1.13), suggesting it is worth investigating lower doses of naltrexone in pregnancy.

This study offers crucial PK insights into LAI naltrexone during pregnancy, which could potentially facilitate informed clinical decision-making regarding naltrexone use and dosing in pregnancy.

Citations: [1] Towers et al. (2020). Am J Obstet Gynecol. https://doi.org/10.1016/j.ajog.2019.07.037
[2] Shenkoya et al. (2023). Pharmaceutics. https://doi.org/10.3390/pharmaceutics15102467