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Monthly injectable naltrexone (XR\u2010NTX) 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\u2010NTX pharmacokinetics during pregnancy, and to predict dosing recommendations. Model predictions were successfully validated with observed data. Maternal plasma XR\u2010NTX profiles were simulated for 400 non\u2010pregnant virtual females at the approved dose of 380\u2009mg, then randomized to continue with either 380, 285, 190, or 95\u2009mg during pregnancy. The non\u2010pregnant virtual females had a mean predicted <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>, AUC<jats:sub>0\u20107days<\/jats:sub>, and AUC<jats:sub>0\u201028days<\/jats:sub> of 23.3\u2009ng\/mL, 142\u2009ng\u00b7d\/mL, and 148\u2009ng\u00b7d\/mL, respectively. Maternal XR\u2010NTX exposure (AUC<jats:sub>0\u201028days<\/jats:sub>) 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\u2010to\u2010maternal exposure (AUC<jats:sub>0\u201028days<\/jats:sub>) was lower in the first (15%), second (7%), and third (9%) trimesters. A dose of 285\u2009mg of XR\u2010NTX in pregnancy during the first\/second trimester and dose of 190\u2009mg in the third trimester were predicted to provide maternal exposures that were comparable to non\u2010pregnant levels at the standard dose. 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