Using PBPK Models to Optimize Anti-HIV Drug Dosing for Pregnant Women

Pregnant women are generally excluded from clinical trials as the risks to the fetus posed by testing most new chemical entities or approved drugs cannot be sufficiently ruled out. As a result, the lack of data on maternal and fetal exposure to drugs complicates selecting treatment options and dosing during pregnancy.

An important example of this is treating pregnant HIV+ patients. HIV-1-positive pregnant women are commonly treated with combination antiretroviral therapy (cART) for their own health and to reduce the risk of perinatal transmission. Pregnancy-related physiological changes can alter the pharmacokinetics (PK) of antiretroviral agents, mostly resulting in reduced drug exposure during pregnancy. Decreased maternal antiretroviral exposure may lead to virologic breakthrough and/or development of antiretroviral resistance and increase the risk of perinatal HIV transmission. Also, excessive dosing may result in maternal and fetal toxicity.

Physiologically-based pharmacokinetic (PBPK) models can help predict maternal and fetal drug exposure based on in vitro pharmacokinetic data, guide dosing of antiretroviral drugs in this special patient population, and improve outcomes for both mother and child. Conversely, clinical pharmacokinetic data on antiviral agents administered to pregnant women provides an excellent opportunity to develop, optimize, and validate pregnancy PBPK models.

In this webinar, we discussed how we combined clinical and pre-clinical approaches to develop a PBPK model to predict the exposure of darunavir, a protease inhibitor commonly used to treat pregnant HIV+ patients. We discussed the integration of in vitro experimental data on drug metabolism and transport with data obtained from ex vivo human placenta perfusion experiments to quantitatively predict both maternal as well as fetal exposure of darunavir. Moreover, we elaborated elaborate on the study design, data collection, and analyses that were used to investigate the clinical pharmacokinetics of antiretroviral agents during pregnancy.

*Angela Colbers and Rick Greupink would like to acknowledge Aaron Buaben, MSc for his help with this project.

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