Optimizing Venlafaxine Therapy in Pregnancy: A Maternal–Fetal PBPK Modeling Approach

Background: Pregnancy-induced physiological changes can substantially alter venlafaxine pharmacokinetics. Despite the clinical relevance of both venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), no physiologically-based pharmacokinetic (PBPK) models have been developed that simultaneously describe their disposition during pregnancy. In this study a PBPK model was developed to predict maternal and fetal exposure to venlafaxine and ODV and to optimize dosing regimens. Methods: PBPK models for venlafaxine and ODV in non-pregnant women, pregnant women, and the fetal–placental unit were developed using the Simcyp^® simulator. Model performance was evaluated using visual predictive checks, assessing whether observed data were contained within the predicted 95% confidence intervals, and by comparing predicted versus observed ratios for maximum plasma concentration (C_max) and area under the concentration–time curve (AUC) using a prespecified range (0.7–1.3). Results: In non-pregnant women, observed venlafaxine and ODV concentrations fell within the 95% confidence intervals of model predictions, with C_max and AUC prediction ratios between 0.7 and 1.3. Most observed data in pregnant women also fell within the 95% confidence intervals. Venlafaxine and ODV concentrations decreased as pregnancy progressed for doses ranging from 37.5 to 225 mg. Cord-to-maternal concentration ratios were approximately 1.02 at 37.5–150 mg and 1.01 at 225 mg. Predicted venlafaxine and ODV concentrations remained within the therapeutic range (100–400 ng/mL) at 150 mg during the first and second trimesters, whereas 225 mg was necessary in the third trimester. At a 375 mg dose, the umbilical cord C_max for venlafaxine reached 195.26 ng/mL, a level approaching thresholds of fetal toxicity. These findings should be interpreted with caution, given the limited sample size in pregnant women (n= 7 for plasma and n=9 for cord blood). Conclusion: A venlafaxine dose of 150 mg/day is recommended during pregnancy, balancing efficacy with the risk of toxicity in both mother and fetus.