Doravirine and the Potential for CYP3A-Mediated Drug-Drug Interactions
- PMID: 30783000
- PMCID: PMC6496093
- DOI: 10.1128/AAC.02016-18
Doravirine and the Potential for CYP3A-Mediated Drug-Drug Interactions
Abstract
Identifying and understanding potential drug-drug interactions (DDIs) are vital for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This article discusses DDIs between doravirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), and cytochrome P450 3A (CYP3A) substrates and drugs that modulate CYP3A activity. Consistent with previously published in vitro data and DDI trials with the CYP3A substrates midazolam and atorvastatin, doravirine did not have any meaningful impact on the pharmacokinetics of the CYP3A substrates ethinyl estradiol and levonorgestrel. Coadministration of doravirine with CYP3A inhibitors (ritonavir or ketoconazole) increased doravirine exposure approximately 3-fold. However, these increases were not considered clinically meaningful. Conversely, previously published trials showed that coadministered CYP3A inducers (rifampin and rifabutin) decreased doravirine exposure by 88% and 50%, respectively (K. L. Yee, S. G. Khalilieh, R. I. Sanchez, R. Liu, et al., Clin Drug Investig 37:659-667, 2017 [https://doi.org/10.1007/s40261-017-0513-4]; S. G. Khalilieh, K. L. Yee, R. I. Sanchez, R. Liu, et al., J Clin Pharmacol 58:1044-1052, 2018 [https://doi.org/10.1002/jcph.1103]), while doravirine exposure following prior efavirenz administration led to an initial reduction in doravirine exposure of 62%, but the reduction became less pronounced with time (K. L. Yee, R. I. Sanchez, P. Auger, R. Liu, et al., Antimicrob Agents Chemother 61:e01757-16, 2017 [https://doi.org/10.1128/AAC.01757-16]). Overall, the coadministration of doravirine with CYP3A inhibitors and substrates is, therefore, supported by these data together with efficacy and safety data from clinical trials, while coadministration with strong CYP3A inducers, such as rifampin, cannot be recommended. Concomitant dosing with rifabutin (a CYP3A inducer less potent than rifampin) is acceptable if doravirine dosing is adjusted from once to twice daily; however, the effect of other moderate inducers on doravirine pharmacokinetics is unknown.
Keywords: HIV; doravirine; drug-drug interactions; nonnucleoside reverse transcriptase inhibitor (NNRTI).
Copyright © 2019 American Society for Microbiology.
Figures
Similar articles
-
Investigation of Pharmacokinetic Interactions between Doravirine and Elbasvir-Grazoprevir and Ledipasvir-Sofosbuvir.Antimicrob Agents Chemother. 2019 Apr 25;63(5):e02491-18. doi: 10.1128/AAC.02491-18. Print 2019 May. Antimicrob Agents Chemother. 2019. PMID: 30782982 Free PMC article.
-
Physiologically Based Pharmacokinetic Modeling of Doravirine and Its Major Metabolite to Support Dose Adjustment With Rifabutin.J Clin Pharmacol. 2021 Mar;61(3):394-405. doi: 10.1002/jcph.1747. Epub 2020 Sep 28. J Clin Pharmacol. 2021. PMID: 32989795 Clinical Trial.
-
Clinical Pharmacodynamics, Pharmacokinetics, and Drug Interaction Profile of Doravirine.Clin Pharmacokinet. 2019 Dec;58(12):1553-1565. doi: 10.1007/s40262-019-00806-9. Clin Pharmacokinet. 2019. PMID: 31388941 Review.
-
Clinical Pharmacokinetics of the Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Doravirine: An Assessment of the Effect of Patient Characteristics and Drug-Drug Interactions.Clin Drug Investig. 2020 Oct;40(10):927-946. doi: 10.1007/s40261-020-00934-2. Clin Drug Investig. 2020. PMID: 32816220 Free PMC article. Review.
-
The Effect of Single and Multiple Doses of Rifampin on the Pharmacokinetics of Doravirine in Healthy Subjects.Clin Drug Investig. 2017 Jul;37(7):659-667. doi: 10.1007/s40261-017-0513-4. Clin Drug Investig. 2017. PMID: 28353169
Cited by
-
Haemopoietic cell transplantation in patients living with HIV.Lancet HIV. 2020 Sep;7(9):e652-e660. doi: 10.1016/S2352-3018(20)30117-X. Epub 2020 Aug 10. Lancet HIV. 2020. PMID: 32791046 Free PMC article. Review.
-
A phase 1, open-label study to evaluate the drug interaction between islatravir (MK-8591) and the oral contraceptive levonorgestrel/ethinyl estradiol in healthy adult females.J Int AIDS Soc. 2021 Dec;24(12):e25858. doi: 10.1002/jia2.25858. J Int AIDS Soc. 2021. PMID: 34935295 Free PMC article. Clinical Trial.
-
Management of Antiretroviral Therapy and Opportunistic Infections in People Living with HIV Undergoing Hematopoietic Stem Cell Transplant in British Columbia.J Assoc Med Microbiol Infect Dis Can. 2024 Dec 19;9(4):249-273. doi: 10.3138/jammi-2024-0013. eCollection 2024 Dec. J Assoc Med Microbiol Infect Dis Can. 2024. PMID: 40672708 Free PMC article.
-
Investigation of Pharmacokinetic Interactions between Doravirine and Elbasvir-Grazoprevir and Ledipasvir-Sofosbuvir.Antimicrob Agents Chemother. 2019 Apr 25;63(5):e02491-18. doi: 10.1128/AAC.02491-18. Print 2019 May. Antimicrob Agents Chemother. 2019. PMID: 30782982 Free PMC article.
-
Approved HIV reverse transcriptase inhibitors in the past decade.Acta Pharm Sin B. 2022 Apr;12(4):1567-1590. doi: 10.1016/j.apsb.2021.11.009. Epub 2021 Nov 16. Acta Pharm Sin B. 2022. PMID: 35847492 Free PMC article. Review.
References
-
- Kaulich-Bartz J, Dam W, May MT, Lederberger B, Widmer U, Phillips AN, Grabar S, Mocroft A, Vilaro J, van Sighem A, Moreno S, Dabis F, Monforte AD, Teira R, Ingle SM, Sterne JA. 2013. Insurability of HIV-positive people treated with antiretroviral therapy in Europe: collaborative analysis of HIV cohort studies. AIDS 27:1641–1655. doi:10.1097/QAD.0b013e3283601199. - DOI - PMC - PubMed
-
- Trickey A, May MT, Vehreschild JJ, Obel N, Gill MJ, Crane HM, Boesecke C, Patterson S, Grabar S, Cazanave C, Cavassini M, Shepherd L, Monforte AD, van Sighem A, Saag M, Lampe F, Hernando V, Montero M, Zangerle R, Justice AC, Sterling T, Ingle SM, Sterne JAC, Boulle A, Stephan C, Miro JM, Chêne G, Costagliola D, Dabis F, del Amo J, Guest J, Haerry DH-U, Hogg R, Justice A, Smith C, Reiss P, Saag M, Teira R, Williams M, May MT. 2017. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies. Lancet HIV 4:e349–e356. doi:10.1016/S2352-3018(17)30066-8. - DOI - PMC - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources