Predicting human foetal exposure using physiologically based pharmacokinetic models
DE SOUSA MENDES Maïlys (1)*, LUI Gabrielle (1),(2), ZHENG Yi (1),(2), PRESSIAT Claire (1) , VALADE Elodie (1), BOUAZZA Naïm (1), FOISSAC Frantz (1), BLANCHE Stephane (1),(4), TRELUYER Jean-Marc (1),(2), BENABOUD Sihem (1),(2), URIEN Saik (1),(3)
(1) EA 7323 : Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Unité de recherche clinique Paris centre, 75006 Paris, France (2) Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin-Broca-Hôtel-Dieu-Dieu, 75014 Paris, France. (3) CIC-1419 Inserm, Cochin-Necker, Paris, France. (4) AP-HP, hôpital Necker-Enfants-malades, unité d'immunologie, hématologie et rhumatologie pédiatriques, 75015 Paris, France * now an employee of Simcyp (a Certara company), Blades Enterprise Centre, John St, Sheffield, UK
Objectives: Pregnant women and their foetuses are exposed to numerous drugs. However, due to obvious ethical reasons in vivo foetal risk assessment studies related to maternal drugs exposure remain extremely limited. The aim of this work was to develop a novel approach to quantitatively predict drug foetal exposure.
Methods: Physiologically based pharmacokinetic (PBPK) models were developed for 3 antiretroviral drugs, tenofovir (TFV), emtricitabine (FTC) and nevirapine (NVP) in Simcyp® for non-pregnant population. All known physiological changes that could impact the drugs PK were taken into account (i.e. change in body weight, glomerular filtration rate, enzymatic activity, plasma volume). After model verification against in vivo concentrations the model was further developed in R software to study foetal exposure. Transplacental transfer parameters were estimated from the ex-vivo human placenta perfusion experiments and then were implemented in the PBPK models. A sensitivity analysis was performed on physiological foetal parameters and transplacental transfer parameters to evaluate their impact on foetal and amniotic fluid PK. Model verification was done by comparing observed maternal and cord blood concentrations to predicted concentrations.
Results: PBPK models successfully predicted the disposition of two renally excreted drug (TFV and FTC) and one metabolized drug (NVP) in pregnant women. The maximum clearance increases were approximately 30% (TFV: 33%, FTC: 31%). Because of CYP3A4, 2D6 and 2B6 inductions, we predicted a clearance increase of 21 % and 38 % in late pregnancy after a single dose administration of NVP and at steady state respectively. Parameters obtained from the ex-vivo experiment allow the prediction of TFV, FTC and NVP concentrations that match observed cord blood concentrations. The foetal-to-maternal AUC ratios (0-24 h interval) were 0.63, 0.41, 0.77 for TFV, FTC and NVP respectively. Physiological foetal parameters as exchanges with amniotic fluid had no significant impact on foetal PK. Therefore, uncertainties on these physiological constants were not a major issue.
Conclusions: PBPK models are useful tool to a priori quantify drug exposure changes during pregnancy. Moreover, the integration of ex-vivo human placental perfusion parameters in these models is a promising new approach for predicting human foetal exposure to xenobiotics in late pregnancy.
