V.E. Bukkems (1), H. van Hove (2), D. Roelofsen (1,2), J.J.M. Freriksen (2), N. van Ewijk-Beneken Kolmer (1), J. van Drongelen (3), R. Greupink (2), A. Colbers (1)
(1) Department of Pharmacy, Radboud Institute of Health Sciences (RIHS), Radboud university medical center, Nijmegen, The Netherlands. (2) Department of Pharmacology & Toxicology, Radboud university medical center, Nijmegen, The Netherlands. (3) Department of Obstetrics and Gynaecology, Radboud university medical center, Nijmegen, The Netherlands
Objectives: Doravirine is a relatively new second-line drug for patients living with HIV. It is regularly used in stable HIV patients because of the favorable side effect profile, low potential for drug interactions, low costs and good efficacy.[1] Adequate antiretroviral therapy is of special importance for pregnant women to prevent mother-to-child transmission of HIV. Currently, doravirine is not recommended for pregnant women due to the lack of efficacy and safety data.[1] Physiological changes during pregnancy can significantly decrease drug exposure, and, thereby, lower the efficacy. The exposure of doravirine may be altered during pregnancy due to a combination of induced CYP3A4 activity, decreased plasma protein concentration and increased renal function among others.[2] This study aimed to assess the efficacy and safety of doravirine in pregnant women by 1) estimating maternal exposure with physiologically-based pharmacokinetic (PBPK) modelling and 2) estimating placental transfer of doravirine via ex vivo human placental cotyledon perfusion experiments and subsequent compartmental modelling.
Methods: To estimate maternal doravirine exposure, an existing and validated three-compartment PBPK model of doravirine for a healthy, non-pregnant population was modified to a full distribution PBPK model using Simcyp Simulator V20.[3] The extended PBPK model was re-validated with independent datasets from single dose, steady state, oral and intravenous studies in non-pregnant healthy individuals.[4-6] The pregnancy population of Simcyp, which has been validated with other drugs metabolized by CYP3A4 [7], was subsequently used to simulate doravirine exposure at 26, 32 and 40 weeks of pregnancy.
To estimate in vivo placental transfer of doravirine, the fetal and maternal circulation (closed-closed) of a human cotyledon were re-established ex vivo. Doravirine (1 mg/L) was added to the maternal (n=4) or fetal circulation (n=4), and antipyrine was added as marker to verify overlap of the cannulated circulations. Samples were taken from the maternal and fetal compartment during 180 minutes of perfusion and analyzed with an LS-MS/MS assay. The fetal-to-maternal (FTM) concentration ratio and mass recovery were calculated at 180 minutes.
Results: The PBPK model predicted that maternal doravirine steady state AUC0-24 decreased by 42%, 50% and 58% compared to non-pregnant women at 26, 32 and 40 weeks of pregnancy, respectively. A geometric mean (GM) C24h of respectively 0.09 mg/L, 0.07 mg/L and 0.05 mg/L was predicted corresponding to a decrease of 68%, 75% and 82% in comparison to non-pregnant women. The predicted GM C24h at 26, 32 and 40 weeks of pregnancy were below 0.23 mg/L (target derived from in vivo exposure-response analysis), but above 0.03 mg/L (target based on 6-fold the in vitro concentration required for 50% inhibition of wild-type HIV-1).[8, 9]
Antipyrine data showed the cannulated circulations overlapped, hence the placental perfusion experiments were considered successful. After addition of doravirine to the maternal circulation, final median (range) concentrations in the maternal and fetal compartments were 0.34 (0.30-0.39) and 0.28 (0.24-0.32) mg/L, respectively, corresponding to a FTM concentration ratio of 0.82. After addition of doravirine to the fetal circulation, final median (range) concentrations were 0.28 (0.24-0.29) and 0.42 (0.40-0.56) mg/L, respectively. The recovery of doravirine was around 50%, indicating placental tissue accumulation of doravirine.
Conclusions: Awaiting clinical data of doravirine during pregnancy, the PBPK model predicts that the maternal doravirine exposure is substantially decreased during pregnancy. This indicates the efficacy of doravirine may be impaired during pregnancy. Therapeutic drug and viral load monitoring are advised for pregnant women treated with doravirine, and the use should preferentially be restricted to clinical trials which are already underway. Placental perfusion experiments showed that doravirine rapidly and extensively crosses the placenta. Furthermore, doravirine seems to accumulate within placental tissue. Nonlinear mixed effect modelling will be used to integrate placental transfer data into the pregnant PBPK model to estimate fetal exposure as well.
References:
[1] EACS. the European Guidelines for the treatment of HIV-positive adults in Europe: version 10.1 2020 [cited 14 April 2021. Available from: https://www.eacsociety.org/files/guidelines-10.1_30032021_1.pdf.
[2] Abduljalil K, Furness P, Johnson TN, Rostami-Hodjegan A, Soltani H. Anatomical, physiological and metabolic changes with gestational age during normal pregnancy: a database for parameters required in physiologically based pharmacokinetic modelling. Clin Pharmacokinet. 2012;51(6):365-96.
[3] Yee KL, Cabalu TD, Kuo Y, Fillgrove KL, Liu Y, Triantafyllou I, et al. Physiologically Based Pharmacokinetic Modeling of Doravirine and Its Major Metabolite to Support Dose Adjustment With Rifabutin. J Clin Pharmacol. 2021;61(3):394-405.
[4] Sanchez RI, Fillgrove KL, Yee KL, Liang Y, Lu B, Tatavarti A, et al. Characterisation of the absorption, distribution, metabolism, excretion and mass balance of doravirine, a non-nucleoside reverse transcriptase inhibitor in humans. Xenobiotica. 2019;49(4):422-32.
[5] Behm MO, Yee KL, Fan L, Fackler P. Effect of gender and age on the relative bioavailability of doravirine: results of a Phase I trial in healthy subjects. Antivir Ther. 2017;22(4):337-44.
[6] Yee KL, Sanchez RI, Auger P, Liu R, Fan L, Triantafyllou I, et al. Evaluation of Doravirine Pharmacokinetics When Switching from Efavirenz to Doravirine in Healthy Subjects. Antimicrob Agents Chemother. 2017;61(2).
[7] Abduljalil K, Pansari A, Jamei M. Prediction of maternal pharmacokinetics using physiologically based pharmacokinetic models: assessing the impact of the longitudinal changes in the activity of CYP1A2, CYP2D6 and CYP3A4 enzymes during pregnancy. Journal of pharmacokinetics and pharmacodynamics. 2020;47(4):361-83.
[8] Yee KL, Ouerdani A, Claussen A, de Greef R, Wenning L. Population Pharmacokinetics of Doravirine and Exposure-Response Analysis in Individuals with HIV-1. Antimicrob Agents Chemother. 2019;63(4).
[9] Khalilieh SG, Yee KL, Sanchez RI, Liu R, Fan L, Martell M, et al. Multiple Doses of Rifabutin Reduce Exposure of Doravirine in Healthy Subjects. J Clin Pharmacol. 2018;58(8):1044-52.
Reference: PAGE 29 (2021) Abstr 9731 [www.page-meeting.org/?abstract=9731]
Poster: Drug/Disease Modelling - Other Topics