Maternal-Fetal Physiologically Based Population Pharmacokinetics Model Development of Lopinavir/Ritonavir in HIV/HBV Co-infected Pregnant Women to Quantitatively Describe the Gestational PK Characteristics and Predict the Potential Disease-Drug-Drug Interaction (DDDI).

Background And Objective: Lopinavir/ritonavir (LPV/r) has been widely used in HIV/HBV co-infected pregnant-women. We aim to characterize the maternal-fetal (m-f) pharmacokinetic (PK) of LPV/r and support the dose optimization and potential drug-drug interaction (DDI) evaluation in this population.

Methods: Lopinavir PK characteristics in human immunodeficiency virus/hepatitis B virus (HIV/HBV) co-infected pregnant women (n = 35) and fetus were calculated using non-compartmental analysis followed by quantification of maternal PK characteristics using population PK (PopPK) analysis. A maternal-fetal lopinavir physiologically based pharmacokinetic (PBPK) model was developed by incorporating trans-placental transfer, disease- and pregnancy-related physiological changes. This final population PBPK model was applied to simulate different dose regimens of LPV/r and potential DDI risks under different drug combination scenarios.

Results: (AUC) of lopinavir in co-infected pregnancy was first reported to be 34.1 and 31.0 mg/L/h for the 2nd and 3rd trimesters. The PBPK-simulated PK parameters were within 0.75 to ~ 1.16-fold of the observations at different stages of pregnancy. The m-f PBPK model-simulated umbilical vein:maternal plasma (UV:MP) ratio of lopinavir was around 0.16 at late trimester, which is consistent with the PopPK model-simulated individual value of 0.116. Simulated results indicated that a standard dose of LPV/r (400/100 mg Q12 h) might not target the effective therapeutic concentration. Model-simulated DDI results suggested that lopinavir increased dose or shortened dosing interval when co-administered with rifampicin in HIV/HBV co-infected pregnancy.

Conclusions: This work successfully applied model-informed approaches to quantitatively assess lopinavir m-f PK and also provided a novel strategy for DDI risk evaluation and dosing optimization for other P-gp substrates in HIV/HBV co-infected pregnant women.