Advancing Precision Drug Therapy in Pregnant Women: PBPK Modeling of Antiviral Drugs

Abstract

Mohamed Abdulsamed, Ashraf A Naass, Mohamed S A Eswani, Mohamed O Elbasir, and Sedigh Bashir

PBPK/PD modeling is essential in modern drug development. Traditional drug development methods frequently rely on trial and error, which can be time-consuming, costly, and could be risky. Predicting pharmacokinetics (PK) of drugs in pregnant women, encompassing the intricate aspect of placental drug transfer, remains a complex task. This study was to compare of simulated or predicted and observed (previously published approaches) pharmacokinetic parameters among the four antiviral drugs in pregnant and non-pregnant women. In addition, this investigation endeavors to construct and assess physiologically-based pharmacokinetic (PBPK) models specific to maternal-fetal interactions for four antiviral drugs, Acyclovir, Emtricitabine, Dolutegravir (DTG) and Raltegravir (RAL). PBPK 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 all 4 a forementioned antiviral maternal plasma concentrations during the 2nd and 3rd trimesters and umbilical vein concentrations at delivery. All clinical in vivo data were obtained from the International Maternal paediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network P1026s study. The PBPK models successfully predicted plasma concentration-time profiles of four antiviral drugs in the 2nd and 3rd trimesters and most predicted PK parameters fell within a 1.33-fold error range. Predicted umbilical vein concentrations of DTG among others were in reasonable agreement with in vivo data but were sensitive to changes in the placental partition coefficient and transplacental clearance. Maternal-fetal PBPK modeling reliably predicted maternal PK of previously mentioned antiviral during pregnancy. For the fetal PK, data on the unbound fraction of highly protein-bound DTG has 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 PK of antiviral. In conclusion, the findings suggest the feasibility of employing physiologically-based pharmacokinetic (PBPK) models to assess the disposition of antiviral drugs in pregnant women and their fetuses.

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