Physiologically based pharmacokinetic modeling of long-acting extended-release naltrexone in pregnant women with opioid use disorder

Abstract

Opioid use disorders (OUD) are a major issue in the U.S. Current treatments for pregnant women, like methadone and buprenorphine require daily dosing and have adverse effects. Monthly injectable naltrexone (XR-NTX) mitigates these adverse effects but is not recommended during pregnancy due to limited pharmacokinetic and safety data. This study developed a physiologically based pharmacokinetic (PBPK) model to describe XR-NTX pharmacokinetics during pregnancy, and to predict dosing recommendations. Model predictions were successfully validated with observed data. Maternal plasma XR-NTX profiles were simulated for 400 non-pregnant virtual females at the approved dose of 380 mg, then randomized to continue with either 380, 285, 190, or 95 mg during pregnancy. The non-pregnant virtual females had a mean predicted C_max, AUC_0-7days, and AUC_0-28days of 23.3 ng/mL, 142 ng·d/mL, and 148 ng·d/mL, respectively. Maternal XR-NTX exposure (AUC_0-28days) were predicted to increase by 1.37, 1.43, and 1.72 times during the first, second, and third trimester of pregnancy. However, the fetal-to-maternal exposure (AUC_0-28days) was lower in the first (15%), second (7%), and third (9%) trimesters. A dose of 285 mg of XR-NTX in pregnancy during the first/second trimester and dose of 190 mg in the third trimester were predicted to provide maternal exposures that were comparable to non-pregnant levels at the standard dose. This study provides crucial insights into XR-NTX pharmacokinetics and proposes a dosing strategy during pregnancy, potentially aiding further clinical investigations and decision making regarding XR-NTX use during pregnancy.