Mechanistic Modeling of Maternal Lymphoid and Fetal Plasma Antiretroviral Exposure During the Third Trimester

Pregnancy-induced changes in plasma pharmacokinetics of many antiretrovirals (ARV) are well-established. Current knowledge about the extent of ARV exposure in lymphoid tissues of pregnant women and within the fetal compartment is limited due to their inaccessibility. Subtherapeutic ARV concentrations in HIV reservoirs like lymphoid tissues during pregnancy may constitute a barrier to adequate virological suppression and increase the risk of mother-to-child transmission (MTCT). The present study describes the pharmacokinetics of three ARVs (efavirenz, dolutegravir, and rilpivirine) in lymphoid tissues and fetal plasma during pregnancy using materno-fetal physiologically-based pharmacokinetic models (m-f-PBPK). Lymphatic and fetal compartments were integrated into our previously validated adult PBPK model. Physiological and drug disposition processes were described using ordinary differential equations. For each drug, virtual pregnant women (n = 50 per simulation) received the standard dose during the third trimester. Essential pharmacokinetic parameters, including Cmax, Cmin, and AUC (0-24), were computed from the concentration-time data at steady state for lymph and fetal plasma. Models were qualified by comparison of predictions with published clinical data, the acceptance threshold being an absolute average fold-error (AAFE) within 2.0. AAFE for all model predictions was within 1.08-1.99 for all three drugs. Maternal lymph concentration 24 h after dose exceeded the reported minimum effective concentration (MEC) for efavirenz (11,514 vs. 800 ng/ml) and rilpivirine (118.8 vs. 50 ng/ml), but was substantially lower for dolutegravir (16.96 vs. 300 ng/ml). In addition, predicted maternal lymph-to-plasma AUC ratios vary considerably (6.431-efavirenz, 0.016-dolutegravir, 1.717-rilpivirine). Furthermore, fetal plasma-to-maternal plasma AUC ratios were 0.59 for efavirenz, 0.78 for dolutegravir, and 0.57 for rilpivirine. Compared with rilpivirine (0 h), longer dose forgiveness was observed for dolutegravir in fetal plasma (42 h), and for efavirenz in maternal lymph (12 h). The predicted low lymphoid tissue penetration of dolutegravir appears to be significantly offset by its extended dose forgiveness and adequate fetal compartment exposure. Hence, it is unlikely to be a predictor of maternal virological failure or MTCT risks. Predictions from our m-f-PBPK models align with recommendations of no dose adjustment despite moderate changes in exposure during pregnancy for these drugs. This is an important new application of PBPK modeling to evaluate the adequacy of drug exposure in otherwise inaccessible compartments.