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

Seo-Yeon Choi,1 Eunsol Yang,2 Kwang-Hee Shin1,3 1College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea; 2Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA; 3Infectious Disease Healthcare, Kyungpook National University, Daegu, Republic of KoreaCorrespondence: Kwang-Hee Shin, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 41566, Republic of Korea, Tel +82 53 950 8582, Fax +82 53 950 8557, Email [email protected]: 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 (Cmax) 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 Cmax 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 Cmax 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. Keywords: venlafaxine, O-desmethylvenlafaxine, pregnancy, PBPK modeling