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 will discuss 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 will discuss 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 will elaborate on the study design, data collection, and analyses that were used to investigate the clinical pharmacokinetics of antiretroviral agents during pregnancy.
About Our Speakers
Dr. Angela Colbers is a biomedical scientist trained at Radboud University Medical Center in Nijmegen, the Netherlands, where she also obtained her PhD in the field of Clinical Pharmacology. Since 1995, she has been involved in clinical trial management, analysis, and reporting. She worked for a pharmaceutical company and contract research organizations. Since 2008, she has worked as a researcher at the department of Pharmacy of the Radboud University Medical Center. The department of Pharmacy of the Radboud University Medical Center has taken the initiative to set up a network of hospitals investigating pharmacokinetics in pregnancy in Europe. Dr. Colbers is project coordinator of a protocol entitled “Study on Pharmacokinetics of newly developed ANtiretroviral agents in HIV-infected pregNAnt women (PANNA)”. In addition, she teaches and advises PhDs and other students on developing and executing clinical trials, and she supports senior scientists with their research.
Dr. Rick Greupink is an Assistant Professor of Pharmacology at Radboud University Medical Center in Nijmegen, the Netherlands. He holds a PharmD from the University of Groningen, the Netherlands, obtained a PhD in Pharmacokinetics and Drug Delivery from the same university and further specialized as a pharmacologist during postdoctoral fellowships in both clinical and pre-clinical settings in the pharmaceutical industry and academia. At the Radboud University Medical Center, Dr. Greupink is faculty in the department of Pharmacology & Toxicology, where his research focuses on investigating the pharmacological roles of drug-transporting membrane proteins in barrier and excretory tissues. The aim is to better understand and predict the impact of drug transporters on clinical pharmacokinetics, drug efficacy, and drug-induced toxicity. In this context, current projects include mechanistic studies on drug disposition in pregnancy, placental transfer, accumulation, and effects of small and large molecule pharmaceuticals.