Clinical Pharmacokinetics

, Volume 58, Issue 12, pp 1553–1565 | Cite as

Clinical Pharmacodynamics, Pharmacokinetics, and Drug Interaction Profile of Doravirine

  • Alison Boyle
  • Catherine E. Moss
  • Catia Marzolini
  • Saye KhooEmail author
Review Article


Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) that has demonstrated good efficacy, tolerability, and safety for the treatment of patients with human immunodeficiency virus (HIV)-1 infection in phase III clinical trials. Doravirine achieved non-inferiority when compared with efavirenz- and darunavir/ritonavir-based regimens. Fewer adverse effects, including neuropsychiatric effects were observed with doravirine compared with efavirenz. Key pharmacodynamic and pharmacokinetic characteristics as well as drug–drug interactions and the resistance profile were assessed in this clinical review. Doravirine is a pyridinone NNRTI with potent antiviral activity against wild-type HIV-1 virus and common NNRTI variants. Studies in healthy volunteers and HIV-infected individuals have shown that doravirine has a favorable pharmacokinetic profile for once-daily dosing, with an elimination half-life of around 15 h, median time to maximum plasma concentrations of 1–4 h, and time to steady-state concentration of 7 days. The pharmacokinetics of doravirine are not greatly influenced by sex, age, race, or hepatic impairment. Although no dose adjustment is required for doravirine in renal impairment when given as a single tablet, the fixed-dose combination tablet of doravirine/lamivudine/tenofovir disoproxil fumarate is not recommended in patients with a creatinine clearance of < 50 mL/min. Doravirine has a low potential for drug–drug interactions and does not impact on the pharmacokinetics of other drugs. However, it is metabolized via cytochrome P450 (CYP) 3A enzymes and is thus susceptible to interactions with CYP3A inhibitors and inducers. Strong CYP3A inhibitors can significantly increase doravirine exposure; however, this is not considered to be clinically relevant. Conversely, strong CYP3A inducers, such as rifampin, are contraindicated with doravirine owing to a significant reduction in exposure with potential for impaired virological efficacy. Moderate CYP3A inducers, such as rifabutin, may be co-administered if the doravirine dose is increased to 100 mg twice daily. Doravirine has a unique resistance profile and has demonstrated in vitro activity against some of the most common, clinically relevant NNRTI-resistant mutations. Prevalence of baseline NNRTI resistance to doravirine appears to be low in treatment-naïve cohorts. Further data on the efficacy of doravirine in patients with previous treatment experience and/or transmitted NNRTI resistance are required to further inform its place in the current armamentarium of drugs for the treatment of HIV infection.


Compliance with Ethical Standards


No sources of funding were received for the preparation of this article.

Conflict of interest

Alison Boyle has received honoraria for lectures from Gilead. Catherine E. Moss has no conflicts of interest that are directly relevant to the content of this article. Catia Marzolini has received research funding from Gilead and honoraria for lectures from MSD. Saye Khoo has received support from ViiV Healthcare, Gilead Sciences, Merck, and Janssen for research, and for the Liverpool Drug Interactions resource.


  1. 1.
    Chaix Baudier M-L, Grudé M, Delagreverie HM, Roussel C, Pere H, Le Guillou-Guillemette H, et al. High prevalence of NNRTI and INI-resistant polymorphic virus in primary HIV infection. Conference on Retroviruses and Opportunistic Infections; 2018; Boston (MA).Google Scholar
  2. 2.
    EACS. EACS guidelines version 9.1. 2018. Accessed 24 Jul 2019.
  3. 3.
    AIDSinfo. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. 2018. Accessed 24 Jul 2019.
  4. 4.
    WHO. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV. 2018. Accessed 24 Jul 2019.
  5. 5.
    Molina JM, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, et al. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018;5(5):e211–20. Scholar
  6. 6.
    Orkin C, Squires KE, Molina JM, Sax PE, Wong WW, Sussmann O, et al. Doravirine/lamivudine/tenofovir disoproxil fumarate is non-inferior to efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults with human immunodeficiency virus-1 infection: week 48 results of the DRIVE-AHEAD trial. Clin Infect Dis. 2019;68(4):535–44. Scholar
  7. 7.
    NIH. Safety and efficacy of a switch to MK-1439A in human immunodeficiency virus (HIV-1)-infected participants virologically suppressed on an anti-retroviral regimen in combination with two nucleoside reverse transcriptase inhibitors (MK-1439A-024) (DRIVE-SHIFT). 2018. Accessed 27 Feb 2019.
  8. 8.
    Cote B, Burch JD, Asante-Appiah E, Bayly C, Bedard L, Blouin M, et al. Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses. Bioorg Med Chem Lett. 2014;24(3):917–22. Scholar
  9. 9.
    El Safadi Y, Vivet-Boudou V, Marquet R. HIV-1 reverse transcriptase inhibitors. Appl Microbiol Biotechnol. 2007;75(4):723–37. Scholar
  10. 10.
    Merck. Pifeltro summary of product characteristics. 2018. Accessed 21 Feb 2019.
  11. 11.
    Lai MT, Feng M, Falgueyret JP, Tawa P, Witmer M, DiStefano D, et al. In vitro characterization of MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor. Antimicrob Agents Chemother. 2014;58(3):1652–63. Scholar
  12. 12.
    Anderson MS, Gilmartin J, Cilissen C, De Lepeleire I, Van Bortel L, Dockendorf MF, et al. Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects. Antivir Ther. 2015;20(4):397–405. Scholar
  13. 13.
    Feng M, Sachs NA, Xu M, Grobler J, Blair W, Hazuda DJ, et al. Doravirine suppresses common nonnucleoside reverse transcriptase inhibitor-associated mutants at clinically relevant concentrations. Antimicrob Agents Chemother. 2016;60(4):2241–7. Scholar
  14. 14.
    Feng M, Wang D, Grobler JA, Hazuda DJ, Miller MD, Lai MT. In vitro resistance selection with doravirine (MK-1439), a novel nonnucleoside reverse transcriptase inhibitor with distinct mutation development pathways. Antimicrob Agents Chemother. 2015;59(1):590–8. Scholar
  15. 15.
    Gupta RK, Gregson J, Parkin N, Haile-Selassie H, Tanuri A, Andrade Forero L, et al. HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis. Lancet Infect Dis. 2018;18(3):346–55. Scholar
  16. 16.
    Molina JM, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, et al. Doravirine (DOR) versus ritonavir-boosted darunavir (DRV + r): 96-week results of the randomized, double-blind, phase 3 DRIVE-FORWARD Noninferiority Trial. 22nd International AIDS Conference; 2018; Amsterdam.Google Scholar
  17. 17.
    Sterrantino G, Borghi V, Callegaro AP, Bruzzone B, Saladini F, Maggiolo F, et al. Prevalence of predicted resistance to doravirine in HIV-1-positive patients after exposure to non-nucleoside reverse transcriptase inhibitors. Int J Antimicrob Agents. 2019;53(4):515–9. Scholar
  18. 18.
    Soulie C, Santoro MM, Charpentier C, Storto A, Paraskevis D, Di Carlo D, et al. Rare occurrence of doravirine resistance-associated mutations in HIV-1-infected treatment-naive patients. J Antimicrob Chemother. 2019;74(3):614–7. Scholar
  19. 19.
    Schurmann D, Sobotha C, Gilmartin J, Robberechts M, De Lepeleire I, Yee KL, et al. A randomized, double-blind, placebo-controlled, short-term monotherapy study of doravirine in treatment-naive HIV-infected individuals. AIDS. 2016;30(1):57–63. Scholar
  20. 20.
    NIH. Safety and efficacy of MK-1439A in participants infected with treatment-naïve human immunodeficiency virus (HIV)-1 with transmitted resistance (MK-1439A-030) (DRIVE BEYOND). 2018. Accessed 07 Apr 2019.
  21. 21.
    NIH. Safety and efficacy of doravirine (MK-1439) in participants with human immunodeficiency virus 1 (HIV-1) (MK-1439-018). U.S. National Library of Medicine, 2018. Accessed 26 Feb 2019.
  22. 22.
    Cohen CJ, Andrade-Villanueva J, Clotet B, Fourie J, Johnson MA, Ruxrungtham K, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. 2011;378(9787):229–37. Scholar
  23. 23.
    Molina JM, Cahn P, Grinsztejn B, Lazzarin A, Mills A, Saag M, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet. 2011;378(9787):238–46. Scholar
  24. 24.
    NIH. Comparison of MK-1439A and ATRIPLA™ in treatment-naive human immunodeficiency virus type 1 (HIV-1)-infected participants (MK-1439A-021). U.S. National Library of Medicine, 2019. Accessed 27 Feb 2019.
  25. 25.
    Orkin C, Squires K, Molina JM, Sax PE, Wong WW, Sussmann O, et al., editors. Doravirine/lamivudine/tenofovir DF continues to be noninferior to efavirenz/emtricitabine/tenofovir DF in treatment-naïve adults with HIV-1 infection: week 96 results of the DRIVE-AHEAD Trial. ID Week; Open Forum Infectious Diseases; 2018; San Francisco (CA).Google Scholar
  26. 26.
    Orkin C, Molina JM, Lombaard J, DeJesus E, Rodgers A, Kumar S, et al. Once-daily doravirine in HIV-1-infected, antiretroviral-naïve adults: an integrated efficacy analysis. Conference on Retroviruses and Opportunistic Infections; 2019; Seattle (WA).Google Scholar
  27. 27.
    Kumar P, Johnson M, Molina J-M, Rizzardini G, Cahn P, Bickel M, et al., editors. Switch to doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) maintains virologic suppression through 48 weeks: results of the DRIVE-SHIFT Trial. ID Week; Open Forum Infectious Diseases; 2018; San Francisco (CA).Google Scholar
  28. 28.
    Maroles-Ramirex JO, Gatell JM, Hagins DP, Thompson M, Arasteh K, Hoffmann C, et al. Safety and antiviral effect of MK-1439, a novel NNRTI (+FTC/TDF) in ART-naive HIV-infected patients. Conference on Retroviruses and Opportunistic Infections; 2014; Boston (MA).Google Scholar
  29. 29.
    Thompson M, Orkin C, Molina JM, Gatell JM, Sax PE, Chan GH, et al. An integrated safety analysis comparing once-daily doravirine (DOR) to darunavir + ritonavir (DRV + r) and efavirenz (EFV) in HIV-1-infected, antiretroviral therapy (ART)-naïve adults. ID Week; 2018; San Franciso (CA).Google Scholar
  30. 30.
    Khalilieh SG, Yee KL, Fan L, Liu R, Heber W, Dunzo E, et al. A randomized trial to assess the effect of doravirine on the QTc interval using a single supratherapeutic dose in healthy adult volunteers. Clin Drug Investig. 2017;37(10):975–84. Scholar
  31. 31.
    EMA. Pifeltro: EPAR—public assessment report 2018. Accessed 29 Apr 2019.
  32. 32.
    Behm MO, Yee KL, Liu R, Levine V, Panebianco D, Fackler P. The effect of food on doravirine bioavailability: results from two pharmacokinetic studies in healthy subjects. Clin Drug Investig. 2017;37(6):571–9. Scholar
  33. 33.
    Sanchez RI, Fillgrove KL, Hafey M, Palamanda J, Newton DJ, Lu B, et al., editors. In vitro evaluation of doravirine potential for pharmacokinetic drug interactions. 20th North American ISSX Meeting; 2015; Orlando (FL).Google Scholar
  34. 34.
    CDER. NDA multi-disciplinary review and evaluation: NDA 210806 and NDA 210807 doravirine (DOR) and DOR/3TC/DOR FDA. 2016.,210807Orig1s000MultidisciplineR.pdf. Accessed 26 Feb 2019.
  35. 35.
    Reitman ML, Chu X, Cai X, Yabut J, Venkatasubramanian R, Zajic S, et al. Rifampin’s acute inhibitory and chronic inductive drug interactions: experimental and model-based approaches to drug–drug interaction trial design. Clin Pharmacol Ther. 2011;89(2):234–42. Scholar
  36. 36.
    Yee KL, Khalilieh SG, Sanchez RI, Liu R, Anderson MS, Manthos H, et al. The effect of single and multiple doses of rifampin on the pharmacokinetics of doravirine in healthy subjects. Clin Drug Investig. 2017;37(7):659–67. Scholar
  37. 37.
    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. Scholar
  38. 38.
    Bleasby K, Fillgrove KL, Houle R, Lu B, Palamanda J, Newton DJ, et al. In vitro evaluation of the drug interaction potential of doravirine. Antimicrob Agents Chemother. 2019;63(4):e02492. Scholar
  39. 39.
    Ankrom W, Yee KL, Sanchez RI, Adedoyin A, Fan L, Marbury T, et al. Severe renal impairment has minimal impact on doravirine pharmacokinetics. Antimicrob Agents Chemother. 2018;62(8):e00326. Scholar
  40. 40.
    Khalilieh S, Yee KL, Liu R, Fan L, Sanchez RI, Auger P, et al. Moderate hepatic impairment does not affect doravirine pharmacokinetics. J Clin Pharmacol. 2017;57(6):777–83. Scholar
  41. 41.
    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):e02502–18. Scholar
  42. 42.
    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. Scholar
  43. 43.
    Khalilieh SG, Yee KL, Sanchez RI, Fan L, Anderson MS, Sura M, et al. Doravirine and the potential for CYP3A-mediated drug–drug interactions. Antimicrob Agents Chemother. 2019;63(5):e02016. Scholar
  44. 44.
    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. ahead of print).CrossRefPubMedGoogle Scholar
  45. 45.
    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):e01757. Scholar
  46. 46.
    Khalilieh SG, Yee KL, Sanchez RI, Fan L, Vaynshteyn K, Deschamps K, et al. A study to evaluate doravirine pharmacokinetics when coadministered with acid-reducing agents. J Clin Pharmacol. 2019. ahead of print).CrossRefPubMedGoogle Scholar
  47. 47.
    Khalilieh S, Yee KL, Sanchez RI, Vaynshteyn K, Deschamps K, Fan L, et al. Co-administration of doravirine with an aluminum/magnesium containing antacid or pantoprazole, a proton pump inhibitor, does not have a clinically meaningful effect on doravirine pharmacokinetics. IAS Conference on HIV Science; 2017; Paris.Google Scholar
  48. 48.
    Khalilieh S, Yee KL, Sanchez RI, Triantafyllou I, Fan L, Maklad N, et al. Results of a doravirine–atorvastatin drug–drug interaction study. Antimicrob Agents Chemother. 2017;61(2):e01364. Scholar
  49. 49.
    Anderson MS, Khalilieh S, Yee KL, Liu R, Fan L, Rizk ML, et al. A two-way steady-state pharmacokinetic interaction study of doravirine (MK-1439) and dolutegravir. Clin Pharmacokinet. 2017;56(6):661–9. Scholar
  50. 50.
    Ankrom W, Sanchez RI, Yee KL, Fan L, Mitra P, Wolford D, et al. Investigation of pharmacokinetic interactions between doravirine and elbasvir/grazoprevir and ledipasvir/sofosbuvir. Antimicrob Agents Chemother. 2019. ahead of print).CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Anderson MS, Khalilieh S, Yee KL, Liu R, Fan L, Rizk ML, et al. Erratum to: A Two-Way Steady-State Pharmacokinetic Interaction Study of Doravirine (MK-1439) and Dolutegravir. Clin Pharmacokinet. 2017;56(6):679–81. Scholar
  52. 52.
    Khalilieh S, Anderson M, Laethem T, Yee K, Sanchez R, Fan L, et al. Multiple-dose treatment with ritonavir increases the exposure of doravirine. Conference on Retroviruses and Opportunistic Infections; 2017; Seattle (WA).Google Scholar
  53. 53.
    Anderson M, Chung C, Tetteh E, Yee K, Guo Y, Fan L, et al., editors. Effect of ketoconazole on the pharmacokinetics of doravirine (MK-1439), a novel non-nucleoside reverse transcriptase inhibitor for the treatment of HIV-1 infection. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; 2015; Washington, DC.Google Scholar
  54. 54.
    Anderson MS, Kaufman D, Castronuovo P, Tetteh E, Yee KL, Liu Y, et al. Effect of doravirine (MK-1439) on the pharmacokinetics of an oral contraceptive (ethinyl estradiol and levonorgestrel). 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; 2015; Washington, DC.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Alison Boyle
    • 1
    • 2
  • Catherine E. Moss
    • 2
  • Catia Marzolini
    • 2
    • 3
  • Saye Khoo
    • 2
    Email author
  1. 1.Department of PharmacyNHS Greater Glasgow and ClydeGlasgowUK
  2. 2.Department of Molecular and Clinical Pharmacology, Institute of Translational MedicineUniversity of LiverpoolLiverpoolUK
  3. 3.Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical ResearchUniversity Hospital BaselBaselSwitzerland

Personalised recommendations