Stein Schalkwijk1,2, Rob ter Heine1, Angela Colbers1, Edmund Capparelli3, Brookie M. Best3, Tim R. Cressey4,5,6, Rick Greupink2, Frans G.M. Russel2, Mark Mirochnick7, Mats O. Karlsson8, and David M. Burger1
1 Department of Pharmacy, Radboud Institute for Health Sciences (RIHS), Radboud university medical center, Nijmegen, The Netherlands 2 Department of Pharmacology & Toxicology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud university medical center, Nijmegen, The Netherlands 3 Skaggs School of Pharmacy and Pharmaceutical Sciences & School of Medicine, University of California San Diego, USA 4 Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand 5 Harvard T.H. Chan School of Public Health, Boston, MA, USA 6 Department of Molecular & Clinical Pharmacology, University of Liverpool, UK 7 Boston University, Boston, MA, USA 8 Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Objectives:
Darunavir is administered as 800 mg once (QD) or 600 mg twice (BID) daily in combination with low-dose (100 mg) ritonavir (pharmacokinetic booster) as part of combination antiretroviral therapy for the treatment of HIV-positive pregnant women (darunavir/r). Therapeutic darunavir exposure in HIV-positive pregnant women is essential to prevent virological breakthrough, development of resistance and HIV transmission from mother to child. However, decreased total darunavir exposure (17%-50%) has been reported during pregnancy and limited data on unbound darunavir exposure are available. It is remains unclear whether standard darunavir/r dosing regimens provide adequate exposure throughout pregnancy. To support and inform the optimal choice of darunavir/r dosing in pregnancy we performed a semi-mechanistic population pharmacokinetic analysis.
Methods:
A simultaneous semi-mechanistic population pharmacokinetic analysis was conducted based on darunavir and ritonavir pharmacokinetic data (intensive sampling) in pregnant and nonpregnant (i.e. postpartum) women. Nonlinear darunavir protein binding was analyzed using a subset of total and unbound darunavir data and integrated in the final model. The final model was used to simulate total and unbound darunavir AUC0-τ, and Ctrough during third trimester of pregnancy, as well as to assess the probability of therapeutic exposure based on reported total and unbound therapeutic targets. In total, 2601 plasma samples were available from 85 women, of which 1643 samples were taken during pregnancy. Corresponding unbound darunavir concentrations were determined in 74 plasma samples from 20 women, during pregnancy and postpartum.
Results:
The final model was developed in three steps. First, the darunavir protein binding dissociation constant and the maximal protein binding capacity were estimated based on nonlinear mixed-effects analysis of paired total and unbound darunavir concentrations in pregnant and nonpregnant women. Then, separate population pharmacokinetic models were developed for ritonavir and darunavir. Thereafter, an integrated pharmacokinetic model was developed, including the darunavir-ritonavir interaction and nonlinear darunavir protein binding. Pregnancy was found to reduce ritonavir relative bioavailability, decrease darunavir protein binding, and increase darunavir intrinsic clearance. As expected, decreased ritonavir exposure in pregnant women resulted in reduced inhibition of intrinsic darunavir clearance. The maximum inhibition (RSE) was 57% (28%) and the half maximal inhibitory ritonavir concentration was 0.09 mg/L (16%). Simulations demonstrated that in the third trimester of pregnancy, total darunavir exposure (AUC0-τ) were 73% and 76% when compared to postpartum for darunavir/r 800/100 mg QD and 600/100 mg BID, respectively. Unbound darunavir AUC0-τ were 90% and 93% compared to postpartum for darunavir/r 800/100 mg QD and 600/100 mg BID, respectively. Unbound darunavir Ctrough were 79% and 88% compared to postpartum for darunavir/r 800/100 mg QD and 600/100 mg BID, respectively. The probability of therapeutic exposure during pregnancy was higher for standard BID dosing (100%) than for QD dosing (95.7%).
Conclusions:
The standard darunavir/r 600/100 mg BID regimen resulted in maximal rates of therapeutic exposure in pregnancy and was superior to 800/100 mg QD in terms of darunavir therapeutic exposure. Darunavir/r 600/100 mg BID should be the preferred regimen during pregnancy unless (adherence) issues dictate QD dosing. The value of alternative dosing regimens for pregnant women seems limited.
Reference: PAGE 27 (2018) Abstr 8729 [www.page-meeting.org/?abstract=8729]
Poster: Drug/Disease Modelling - Infection