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O36 Physiologically based pharmacokinetic models to predict fetal exposure to antiviral drugs

Background Physiologic changes associated with pregnancy may have a large impact on drug disposition. The goal of this study was to build PBPK maternal-fetal models to predict the fetal exposure to antiviral drugs including emtricitabine and acyclovir. Methods PBPK models were built in the Open Systems Pharmacology Software Suite version 7.3 (www.open-systems-pharmacology.org). The maternal-fetal PBPK model structure was developed in MoBi and exported to PK-Sim for population simulations. Placental transfer was parameterized based on data from ex vivo cotyledon perfusion experiments. The predictive performance of the PBPK models was evaluated via comparison with in vivo data. The pregnancy data for those drugs were from in vivo maternal and fetal blood samples taken at delivery. Results In the acyclovir ex vivo experimental data simulation, the fitted was 0.056 L/h (95% confidence interval: 0.043 - 0.069 L/h) and the fitted was 0.49 (95% confidence interval: 0.39 - 0.59). The predicted ratio between acyclovir in vivo concentrations in the umbilical vein plasma and the maternal plasma ranged from 0.37 - 0.77, whereas the observed ratios were slightly higher and ranged from 0.61 - 1.1.1 The previously published, and CLpl (1.49 1/h) parameters2 were applied to the emtricitabine maternal-fetal PBPK model, and the emtricitabine concentrations in the umbilical cord were adequately predicted. Conclusion These results increase the confidence in applying PBPK models to predict maternal and fetal drug exposure. Improved maternal-fetal PBPK models may streamline and accelerate the performance of pharmacokinetic and safety studies for drugs in pregnant women. References Frenkel LM, et al. Pharmacokinetics of acyclovir in the term human pregnancy and neonate. Am J Obstet Gynecol 1991;164:569–76. De Sousa Mendes M, et al. Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models. Brit J Clin Pharmacol 2016;81:646–57. Disclosure(s) The opinions expressed in this article are those of the authors and should not be interpreted as the position of the U.S. Food and Drug Administration or of the National Institutes of Health. The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.