Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Aug;61(8):1129-1141.
doi: 10.1007/s40262-022-01127-0. Epub 2022 May 17.

Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments

V E Bukkems  1 , H van Hove  2 , D Roelofsen  3   2 , J J M Freriksen  2 , E W J van Ewijk-Beneken Kolmer  3 , D M Burger  3 , J van Drongelen  4 , E M Svensson  3   5 , R Greupink #  2 , A Colbers #  3
Affiliations
Free PMC article

Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments

V E Bukkems et al. Clin Pharmacokinet. 2022 Aug.
Free PMC article

Abstract

Background and objective: Doravirine is currently not recommended for pregnant women living with human immunodeficiency virus because efficacy and safety data are lacking. This study aimed to predict maternal and fetal doravirine exposure by integrating human placenta perfusion experiments with pregnancy physiologically based pharmacokinetic (PBPK) modeling.

Methods: Ex vivo placenta perfusions were performed in a closed-closed configuration, in both maternal-to-fetal and fetal-to-maternal directions (n = 8). To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy. The predicted total geometric mean (GM) trough plasma concentration (Ctrough) values were compared with the target (0.23 mg/L) derived from in vivo exposure-response analysis.

Results: A decrease of 55% in maternal doravirine area under the plasma concentration-time curve (AUC)0-24h was predicted in pregnant women at 40 weeks of pregnancy compared with nonpregnant women. At 26, 32, and 40 weeks of pregnancy, predicted maternal total doravirine GM Ctrough values were below the predefined efficacy target of 0.23 mg/L. Perfusion experiments showed that doravirine extensively crossed the placenta, and PBPK modeling predicted considerable fetal doravirine exposure.

Conclusion: Substantially reduced maternal doravirine exposure was predicted during pregnancy, possibly resulting in impaired efficacy. Therapeutic drug and viral load monitoring are advised for pregnant women treated with doravirine. Considerable fetal doravirine exposure was predicted, highlighting the need for clinical fetal safety data.

PubMed Disclaimer

Conflict of interest statement

AC has received honoraria from Merck Sharp & Dohme Corp 2021, paid to their institution. A Colbers and D Burger have received study grants from Merck Sharp & Dohme Corp, Gilead, and ViiV Healthcare, paid to their institution. VE Bukkems, H van Hove, D Roelofsen, JJM Freriksen, EWJ van Ewijk-Beneken Kolmer, J van Drongelen, EM Svensson, and R Greupink have no conflicts of interest that are directly relevant to the content of this article.

Figures

Fig. 1
Fig. 1
Schematic overview of the tested mechanistic placenta model structures to estimate intrinsic placental transfer parameters of doravirine based on ex vivo perfusion data in closed–closed configuration. A simple diffusion transfer model; (B) diffusion model combined with p-glycoprotein-mediated active transport over the maternal-facing barrier. CLpdf clearance between fetal part of the placenta and the placental barrier, CLpdm clearance between maternal part of the placenta and the placental barrier, CLP-GP p-glycoprotein-mediated active transport, FR fetal reservoir, FP fetal part of the placenta, PB barrier of the placenta, MP maternal part of the placenta, MR maternal reservoir
Fig. 2
Fig. 2
Structure of the pregnancy physiologically based pharmacokinetic (PBPK) model in the PBPK platform Simcyp
Fig. 3
Fig. 3
Placental transfer of doravirine determined with ex vivo human cotyledon perfusion experiments in closed–closed configuration (n = 4 each). Data are shown as mean ± standard deviation
Fig. 4
Fig. 4
Predicted mean doravirine total plasma concentration at steady state after treatment with A, B doravirine 100 mg QD or C, D 100 mg BID using the pregnancy physiologically based pharmacokinetic model (n = 100 subjects). The in vivo target of 0.23 mg/L was derived from in vivo exposure–response analysis [33]. BID twice daily, QD once daily, w weeks
Fig. 5
Fig. 5
Sensitivity analysis of the estimated placental parameters using the pregnancy physiologically based pharmacokinetic model (n = 100 subjects). Sensitivity of CLpdm input on the doravirine A maternal plasma concentration and B fetal venous blood concentration. Sensitivity of CLpdf input on the doravirine, C maternal plasma concentration and D fetal venous blood concentration. The 2.5th and 97.5th percentile of the typical CLpdf and CLpdm are estimated with the mechanistic placenta model. Sensitivity of the FUp impute on the doravirine, E maternal plasma concentration and F fetal venous blood concentration. Sensitivity of the experimental placenta perfusion configuration on the doravirine, G maternal plasma concentration and H fetal venous blood concentration. CLpdf clearance between fetal part of the placenta and the placental barrier, CLpdm clearance between maternal part of the placenta and the placental barrier, FUP fraction unbound in the placental barrier
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Blehar MC, Spong C, Grady C, Goldkind SF, Sahin L, Clayton JA. Enrolling pregnant women: issues in clinical research. Womens Health Issues. 2013;23(1):e39–45. doi: 10.1016/j.whi.2012.10.003. - DOI - PMC - PubMed
    1. Colbers A, Mirochnick M, Schalkwijk S, Penazzato M, Townsend C, Burger D. Importance of prospective studies in pregnant and breastfeeding women living with human immunodeficiency virus. Clin Infect Dis. 2019;69(7):1254–1258. doi: 10.1093/cid/ciz121. - DOI - PMC - PubMed
    1. Hodel EM, Marzolini C, Waitt C, Rakhmanina N. Pharmacokinetics, placental and breast milk transfer of antiretroviral drugs in pregnant and lactating women living with HIV. Curr Pharm Des. 2019;25(5):556–576. doi: 10.2174/1381612825666190320162507. - DOI - PubMed
    1. EACS. the European Guidelines for the treatment of HIV-positive adults in Europe: version 11.0. 2021. https://www.eacsociety.org/media/final2021eacsguidelinesv11.0_oct2021.pdf. Accessed 1 Nov 2021.
    1. 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. doi: 10.1002/jcph.1747. - DOI - PubMed

Publication types

LinkOut - more resources