Prediction of Maternal and Fetal Pharmacokinetics of Dolutegravir and Raltegravir Using Physiologically Based Pharmacokinetic Modeling

[AndreDlm]

https://pubmed.ncbi.nlm.nih.gov/32451908/ Liu XI, Momper JD, Rakhmanina NY, Green DJ, Burckart GJ, Cressey TR, Mirochnick M, Best BM, van den Anker JN, Dallmann A. Prediction of Maternal and Fetal Pharmacokinetics of Dolutegravir and Raltegravir Using Physiologically Based Pharmacokinetic Modeling. Clinical Pharmacokinetics 2020. DOI: 10.1007/s40262-020-00897-9 [ePub ahead of print].

Abstract Background: Predicting drug pharmacokinetics in pregnant women including placental drug transfer remains challenging. This study aimed to develop and evaluate maternal–fetal physiologically based pharmacokinetic models for two antiretroviral drugs, dolutegravir and raltegravir. Methods: Physiologically based pharmacokinetic models were built with the Open Systems Pharmacology software suite (PK-Sim®/MoBi®). Different approaches to inform placental drug transfer were applied and compared. Model performance was evaluated using in vivo dolutegravir and raltegravir maternal plasma concentrations during the second and third trimesters and umbilical vein concentrations at delivery. All clinical in vivo data were obtained from the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network P1026s study. Results: The physiologically based pharmacokinetic models successfully predicted plasma concentration–time profiles of dolutegravir and raltegravir in the second and third trimesters and predicted pharmacokinetic parameters fell mostly within a 1.33-fold error range. Predicted umbilical vein concentrations of dolutegravir were in reasonable agreement with in vivo data but were sensitive to changes in the placental partition coefficient and transplacental clearance. Conclusions: Maternal–fetal physiologically based pharmacokinetic modeling reliably predicted maternal pharmacokinetics of dolutegravir and raltegravir during pregnancy. For the fetal pharmacokinetics, data on the unbound fraction of highly protein-bound dolutegravir have proven to be important to adequately capture changes in total clearance in silico. More research efforts, along with clinical data, are needed to verify the predictions of fetal pharmacokinetics of antiretroviral drugs. Overall, the findings suggest that it may be possible to use physiologically based pharmacokinetic models to assess the disposition of antiretroviral drugs in pregnant women and their fetuses.

[AndreDlm]

The PBPK model files for dolutegravir and raltegravir can be found in the Pregnancy-Model repository