Pharmacokinetics, Antiviral Activity, and Safety of Rilpivirine in Pregnant Women with HIV-1 Infection: Results of a Phase 3b, Multicenter, Open-Label Study

Olayemi Osiyemi, Salih Yasin, Carmen Zorrilla, Ceyhun Bicer, Vera Hillewaert, Kimberley Brown, Herta M Crauwels, Olayemi Osiyemi, Salih Yasin, Carmen Zorrilla, Ceyhun Bicer, Vera Hillewaert, Kimberley Brown, Herta M Crauwels

Abstract

Introduction: Physiologic changes during pregnancy may impact the pharmacokinetics of drugs. In addition, efficacy and safety/tolerability concerns have been identified for some antiretroviral agents.

Methods: Human immunodeficiency virus (HIV)-1-infected pregnant women (18-26 weeks gestation) receiving the non-nucleoside reverse transcriptase inhibitor rilpivirine 25 mg once daily were enrolled in this phase 3b, open-label study examining the impact of pregnancy on the pharmacokinetics of rilpivirine when it is given in combination with other antiretroviral agents. Blood samples (collected over the 24-h dosing interval) to assess total and unbound rilpivirine plasma concentrations were obtained during the second and third trimesters (24-28 and 34-38 weeks gestation, respectively) and 6-12 weeks postpartum. Pharmacokinetic parameters were derived using noncompartmental analysis and compared (pregnancy versus postpartum) using linear mixed effects modeling. Antiviral and immunologic response and safety were assessed.

Results: Nineteen women were enrolled; 15 had evaluable pharmacokinetic results. Total rilpivirine exposure was 29-31% lower during pregnancy versus postpartum; differences were less pronounced for unbound (pharmacodynamically active) rilpivirine. At study entry, 12/19 (63.2%) women were virologically suppressed; 10/12 (83.3%) women were suppressed at the postpartum visit. Twelve infants were born to the 12 women who completed the study (7 discontinued); no perinatal viral transmission was observed among 10 infants with available data. Rilpivirine was generally safe and well tolerated in women and infants exposed in utero.

Conclusion: Despite decreased rilpivirine exposure during pregnancy, treatment was effective in preventing mother-to-child transmission and suppressing HIV-1 RNA in pregnant women. Results suggest that rilpivirine 25 mg once daily, as part of individualized combination antiretroviral therapy, may be an appropriate option for HIV-1-infected pregnant women.

Trial registration: ClinicalTrials.gov Identifier, NCT00855335.

Keywords: HIV; Pharmacokinetics; Pregnancy; Rilpivirine.

Figures

Fig. 1
Fig. 1
Mean (±SD) plasma concentration–time profiles of total rilpivirine during pregnancy and postpartum over the 24-h dosing interval. SD standard deviation
Fig. 2
Fig. 2
Antiviral activity over time, as assessed by a HIV-1 RNA* and b CD4+ percentage during pregnancy and postpartum. HIV-1 human immunodeficiency virus-1, qd once daily, ARV antiretroviral. *For each time point, percentages may not total 100% due to rounding. †The baseline visit occurred at 18–26 weeks gestation; per the inclusion criteria, eligible subjects were receiving rilpivirine 25 mg qd as part of their ARV regimen at the time of study entry

References

    1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Department of Health and Human Services. . Accessed 17 Oct 2017.
    1. Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States. . Accessed 30 Nov 2017.
    1. Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44(10):989–1008. doi: 10.2165/00003088-200544100-00001.
    1. Gilbert EM, Darin KM, Scarsi KK, et al. Antiretroviral pharmacokinetics in pregnant women. Pharmacotherapy. 2015;35(9):838–855. doi: 10.1002/phar.1626.
    1. Zorrilla CD, Wright R, Osiyemi OO, et al. Total and unbound darunavir pharmacokinetics in pregnant women infected with HIV-1: results of a study of darunavir/ritonavir 600/100 mg administered twice daily. HIV Med. 2014;15(1):50–56. doi: 10.1111/hiv.12047.
    1. Crauwels HM, Kakuda TN, Ryan B, et al. Pharmacokinetics of once-daily darunavir/ritonavir in HIV-1-infected pregnant women. HIV Med. 2016;17(9):643–652. doi: 10.1111/hiv.12366.
    1. Lamorde M, Byakika-Kibwika P, Okaba-Kayom V, et al. Suboptimal nevirapine steady-state pharmacokinetics during intrapartum compared with postpartum in HIV-1-seropositive Ugandan women. J Acquir Immune Defic Syndr. 2010;55(3):345–350. doi: 10.1097/QAI.0b013e3181e9871b.
    1. Cressey TR, Stek A, Capparelli E, et al. Efavirenz pharmacokinetics during the third trimester of pregnancy and postpartum. J Acquir Immune Defic Syndr. 2012;59(3):245–252. doi: 10.1097/QAI.0b013e31823ff052.
    1. Ramgopal M, Osiyemi O, Zorrilla C, et al. Pharmacokinetics of total and unbound etravirine in HIV-1-infected pregnant women. J Acquir Immune Defic Syndr. 2016;73(3):268–274. doi: 10.1097/QAI.0000000000001068.
    1. Mulligan N, Schalkwijk S, Best BM, et al. Etravirine pharmacokinetics in HIV-infected pregnant women. Front Pharmacol. 2016;7:239. doi: 10.3389/fphar.2016.00239.
    1. Schalkwijk S, Colbers A, Konopnicki D, et al. Lowered rilpivirine exposure during the third trimester of pregnancy in human immunodeficiency virus type 1-infected women. Clin Infect Dis. 2017;65(8):1335–1341.
    1. Tran AH, Best BM, Stek A, et al. Pharmacokinetics of rilpivirine in HIV-infected pregnant women. J Acquir Immune Defic Syndr. 2016;72(3):289–296. doi: 10.1097/QAI.0000000000000968.
    1. EDURANT® (rilpivirine) [package insert]. Titusville: Janssen Therapeutics; 2015.
    1. Cohen CJ, Molina JM, Cahn P, et al. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials. J Acquir Immune Defic Syndr. 2012;60(1):33–42. doi: 10.1097/QAI.0b013e31824d006e.
    1. Nelson MR, Elion RA, Cohen CJ, et al. Rilpivirine versus efavirenz in HIV-1-infected subjects receiving emtricitabine/tenofovir DF: pooled 96-week data from ECHO and THRIVE studies. HIV Clin Trials. 2013;14(3):81–91. doi: 10.1310/hct1403-81.
    1. Palella FJ, Jr, Fisher M, Tebas P, et al. Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants. AIDS. 2014;28(3):335–344. doi: 10.1097/QAD.0000000000000087.
    1. Orkin C, DeJesus E, Ramgopal M, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-interfority study. Lancet HIV. 2017;4(5):e195–e204. doi: 10.1016/S2352-3018(17)30031-0.
    1. DeJesus E, Ramgopal M, Crofoot G, et al. Switching from efavirenz, emtricitabine, and tenofovir disproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study. Lancet HIV. 2017
    1. European AIDS Clinical Society. EACS guidelines, version 9.0. 2017.
    1. Antiretroviral Pregnancy Registry Steering Committee . Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 January 2017. Wilmington: Registry Coordinating Center; 2017.
    1. COMPLERA® (emtricitabine, rilpivirine, tenofovir disoproxil fumarate) [package insert]. Foster City: Gilead Sciences; 2016.
    1. Towers CV, Rumney PJ, Ghamsary MG. Longitudinal study of CD4+ cell counts in HIV-negative pregnant patients. J Matern Fetal Neonatal Med. 2010;23(10):1091–1096. doi: 10.3109/14767050903580359.
    1. Notarianni LJ. Plasma protein binding of drugs in pregnancy and in neonates. Clin Pharmacokinet. 1990;18(1):20–36. doi: 10.2165/00003088-199018010-00002.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe