Drug information

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Pronounce:
Other Names:
DAP, DPV, DVR, DVR-004, Ring-004, TMC-120, dapivirine IVR, dapivirine intravaginal ring, DPV-VR
Drug Class:
Microbicides
Molecular Formula:

C20 H19 N5

Registry Number:
244767-67-7 (CAS)
Chemical Name:

4-[[4-(2,4,6-trimethylanilino)pyrimidin-2-yl]amino]benzonitrile

Chemical Class:
Pyrimidines
Organization:
Janssen Pharmaceutical Companies of Johnson & Johnson; International Partnership for Microbicides (IPM)
Phase of Development:

The monthly dapivirine intravaginal ring has completed Phase 3b testing as a product for HIV prevention. The drug sponsor is currently seeking regulatory approval of the monthly dapivirine ring in sub-Saharan Africa. The dapivirine ring is also under review by the U.S. Food and Drug Administration (FDA).

Chemical Image: (Click to enlarge)

dapivirine

Molecular Weight: 329.405

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 International Partnership for Microbicides [IPM] publication,3 and IPM website4)

Pharmacology

Pharmacology

Mechanism of Action: Microbicide; non-nucleoside reverse transcriptase inhibitor (NNRTI). HIV-specific topical microbicides formulated with antiretroviral (ARV) drugs, such as dapivirine, are being developed as a pre-exposure prophylaxis (PrEP) strategy to prevent the sexual transmission of HIV. ARV-based topical microbicides are designed to inhibit infection at the vaginal or rectal mucosa and directly interfere with the HIV replication cycle.5-8

Dapivirine, a substituted diarylpyrimidine derivative, irreversibly binds to and inhibits HIV reverse transcriptase, preventing the conversion of viral RNA to proviral DNA. Because of dapivirine’s tight binding and lipophilic characteristics, it may be active against both cell-free and cell-associated HIV.9,10 The dapivirine vaginal ring inhibits HIV locally, primarily within CD4 cells in the tissues of the female lower reproductive tract.11

Several different dapivirine-based microbicide products have been studied in clinical trials. The monthly dapivirine intravaginal ring (IVR) is the furthest along in development and has completed Phase 3b trials.3,4

In July 2020, the European Medicines Agency (EMA) provided a positive opinion on the use of the dapivirine IVR in cisgender women who are 18 and older in developing countries to reduce the risk of HIV infection. Additionally, in January 2021, the World Health Organization (WHO) recommended that the monthly dapivirine IVR may be offered as an additional prevention choice for women at substantial risk of HIV infection. The drug sponsor is currently seeking regulatory approval of the monthly dapivirine ring in sub-Saharan Africa and the United States.3,12

Half-life (T½): In clinical trials evaluating the dapivirine vaginal ring, the terminal elimination half-life of dapivirine was determined to be approximately 82 hours in plasma and 13 hours in cervical vaginal fluid.11

Metabolism/Elimination: Orally administered dapivirine undergoes extensive metabolism in the liver, primarily via oxidation by CYP enzymes (mainly CYP3A, with contributions from CYP2B6 and 2C19) and secondarily via glucuronidation by UGT enzymes (UGT1A and 2B). Studies with human vaginal tissue samples indicate that CYP enzymes, but not UGT enzymes, are locally expressed and active in vaginal tissues; therefore, dapivirine exposures in human vaginal tissue may vary due to CYP metabolism.11

Resistance: Results from two Phase 3 clinical trials (Ring study; NCT01539226 and ASPIRE study; NCT01617096) found that use of the dapivirine IVR did not appear to increase ARV-resistant HIV among participants who acquired HIV.13-15 However, among participants who acquired HIV in the Ring study, the E138A substitution (an HIV-1 subtype C polymorphism) was noted to occur more frequently in dapivirine participants than in placebo participants.16 In the ASPIRE trial, this mutation was found to occur at a similar frequency in both study groups and was determined to be unlikely to cause a reduction in IVR efficacy. In addition, follow-up from ASPIRE found that the effectiveness of standard recommended NNRTI-containing ART regimens in participants who had acquired HIV during the study was not impacted by dapivirine IVR use.17,18

Select Clinical Trials

Select Clinical Trials

Dapivirine-Based IVR

Study Identifiers: (1) Ring Study; IPM 027; NCT01539226 and (2) DREAM Study; IPM 032; NCT02862171
Sponsor: International Partnership for Microbicides, Inc.
Phase: The Ring study was a Phase 3 trial, and the DREAM study was a follow-on Phase 3b trial.
Status: The Ring and DREAM studies have both been completed.
Study Purpose: The Ring study was designed to evaluate the safety and efficacy of a monthly dapivirine silicone elastomer matrix IVR (Ring-004) for the prevention of HIV infection in women. The DREAM study was an open-label follow-on study that continued to evaluate dapivirine safety and participant adherence in women who were enrolled in the Ring study.
Study Population:

  • Participants in the Ring study were HIV-negative, sexually active women 18 to 45 years of age from South Africa and Uganda.
  • Participants in the DREAM study were HIV-negative women who previously participated in the Ring study.14,16,19,20

Selected Study Results:


Study Identifiers: (1) ASPIRE Study; MTN-020; NCT01617096 and (2) HOPE Study; MTN-025; NCT02858037
Sponsor: International Partnership for Microbicides, Inc.
Phase: ASPIRE was a Phase 3 trial, and HOPE was a Phase 3b follow-on trial.
Status: The ASPIRE and HOPE studies have both been completed.
Study Purpose: The ASPIRE study was designed to evaluate the safety and effectiveness of a dapivirine silicone elastomer matrix IVR (Ring-004) for the prevention of HIV infection in women. HOPE was an open-label follow-on study that continued to evaluate dapivirine safety and participant adherence in women who were enrolled in ASPIRE.
Study Population:
  • Participants in the ASPIRE study were HIV-negative, sexually active women 18 to 45 years of age from Malawi, South Africa, Uganda, and Zimbabwe.
  • Participants in the HOPE study were HIV-negative women who previously participated in ASPIRE.15,21
Selected Study Results:


Additional dapivirine-based IVR studies have also been completed or are ongoing or planned.22 These include the following trials:

  • MTN-036/IPM 047 (NCT03234400): A completed Phase 1 pharmacokinetic and safety study that evaluated extended duration dapivirine rings.23
  • MTN-044/IPM 053/CCN019 (NCT03467347): A completed Phase 1 pharmacokinetic and safety study that assessed a combination IVR containing dapivirine and levonorgestrel.24
  • REACH; MTN-034 (NCT03593655): A Phase 2a study evaluating the safety of and adherence to the monthly dapivirine IVR and oral emtricitabine/tenofovir DF in adolescent and young adult female participants. This study is ongoing, but not recruiting participants.25,26
  • MTN-042 (NCT03965923): A Phase 3b trial assessing the safety of the dapivirine IVR and oral emtricitabine/tenofovir DF (Truvada) when used during pregnancy. This study is currently recruiting participants.27
  • MTN-043 (NCT04140266): A Phase 3b trial assessing the safety and drug detection of the dapivirine IVR and Truvada in breastfeeding mother-infant pairs. This study is currently recruiting participants.28

Other Dapivirine-Based Microbicide Formulations

Other dapivirine-based microbicide formulations have been studied, including a vaginal film (Phase 1) and gel administered rectally (Phase 1) or vaginally (Phase 2). A combination vaginal gel containing dapivirine and darunavir has also been studied in a Phase 1 trial.4,29,30

Adverse Events

Adverse Events


Ring study (NCT01539226); DREAM study (NCT02862171):

In the Phase 3 Ring study, dapivirine IVR use in women was reported to be safe, with a similar rate of adverse events (AEs) in both the active drug and placebo arms.13,16 No dapivirine-related serious adverse events (SAEs) or Grade 3 or 4 AEs occurred. AEs related to dapivirine IVR included metrorrhagia, pelvic discomfort/pain, suprapubic pain, and application site pain, all of which were mild in severity.16

Results from the open-label follow-on DREAM study showed a comparable safety profile to what was seen in the Ring study. Among 941 participants who enrolled in the DREAM study, approximately 66% experienced an AE. Only six participants (<1%) experienced an AE that was considered to be related to the study product. There were no treatment-related SAEs.31

ASPIRE study (NCT01617096); HOPE study (NCT02858037):

Similarly, in the Phase 3 ASPIRE study, dapivirine IVR use in women was also reported to be safe, with a similar rate of AEs in both the active drug and placebo arms.13,32 Again, no dapivirine-related SAEs or Grade 3 or 4 AEs occurred. Dapivirine-related AEs included moderate cervicitis, urinary tract infection, headache, urinary incontinence, cervix erythema and oedema, dyspareunia, and pelvic pain.32

The open-label follow-on HOPE trial demonstrated a safety profile similar to that of the ASPIRE trial. Among 1,456 enrolled participants, no dapivirine-related SAEs or Grade 3 or higher AEs occurred. Dapivirine-related Grade 2 AEs occurred in just two participants (<1%).21,33

Drug Interactions

Drug Interactions

A drug-drug interaction study between dapivirine IVR (Ring-004) and miconazole nitrate (1200-mg vaginal capsule) found that concomitant use caused local and systemic changes to levels of both drugs; however, such changes are not likely to alter the effectiveness of either drug.34

In the ASPIRE trial (NCT01617096), investigators evaluated whether the dapivirine IVR would alter the effectiveness of hormonal contraception. Among women who were receiving various forms of hormonal contraception during the study, no difference in pregnancy incidence between the dapivirine group and the placebo group was seen.35

References

References

  1. United States National Library of Medicine. ChemIDplus advanced: Dapivirine. https://chem.nlm.nih.gov/chemidplus/rn/244767-67-7. Accessed June 1, 2021
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed June 1, 2021
  3. International Partnership for Microbicides (IPM). A long-acting ring for women’s HIV prevention. https://www.ipmglobal.org/sites/default/files/media_block_files/ipm_ring_backgrounder_mar_2021.pdf. Accessed June 1, 2021
  4. International Partnership for Microbicides (IPM) website. Our products. https://www.ipmglobal.org/our-work/product-pipeline. Accessed June 1, 2021
  5. National Institute of Allergy and Infectious Diseases (NIAID). Microbicides to block transmission of HIV. https://www.niaid.nih.gov/diseases-conditions/microbicides. Accessed June 1, 2021
  6. Shattock RJ, Rosenberg Z. Microbicides: topical prevention against HIV. Cold Spring Harb Perspect Med. 2012;2(2):a007385.
  7. Balzarini J, Van Damme L. Intravaginal and intrarectal microbicides to prevent HIV infection. CMAJ. 2005;172(4):461-464. doi:10.1503/cmaj.1041462
  8. Adams JL, Kashuba AD. Formulation, pharmacokinetics and pharmacodynamics of topical microbicides. Best Pract Res Clin Obstet Gynaecol. 2012;26(4):451-462. doi:10.1016/j.bpobgyn.2012.01.004
  9. Garg AB, Nuttall J, Romano J. The future of HIV microbicides: challenges and opportunities. Antivir Chem Chemother. 2009;19(4):143-150. doi:10.1177/095632020901900401
  10. Nuttall JP, Thake DC, Lewis MG, Ferkany JW, Romano JW, Mitchnick MA. Concentrations of dapivirine in the rhesus macaque and rabbit following once daily intravaginal administration of a gel formulation of [14C] dapivirine for 7 days. Antimicrob Agents Chemother. 2008;52(3):909-914. doi:10.1128/AAC.00330-07
  11. European Medicines Agency (EMA). Assessment report: dapivirine vaginal ring 25 mg. July 23, 2020. https://www.ema.europa.eu/en/documents/medicine-outside-eu/dapivirine-vaginal-ring-25-mg-public-assessment-report_en.pdf. Accessed June 1, 2021
  12. World Health Organization (WHO): News, dated January 26, 2021. WHO recommends the dapivirine vaginal ring as a new choice for HIV prevention for women at substantial risk of HIV infection. https://www.who.int/news/item/26-01-2021-who-recommends-the-dapivirine-vaginal-ring-as-a-new-choice-for-hiv-prevention-for-women-at-substantial-risk-of-hiv-infection. Accessed June 1, 2021
  13. International Partnership for Microbicides (IPM): Press Release, dated February 22, 2016. Two large studies show IPM’s monthly vaginal ring helps protect women against HIV. https://www.ipmglobal.org/publications/two-large-studies-show-ipm’s-monthly-vaginal-ring-helps-protect-women-against-hiv. Accessed June 1, 2021
  14. International Partnership for Microbicides, Inc. A multi-centre, randomised, double-blind, placebo-controlled safety and efficacy trial of a dapivirine vaginal matrix ring in healthy HIV-negative women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 21, 2012. NLM Identifier: NCT01539226. https://clinicaltrials.gov/ct2/show/NCT01539226. Accessed June 1, 2021
  15. International Partnership for Microbicides, Inc. A multi-center, randomized, double-blind, placebo-controlled Phase 3 safety and effectiveness trial of a vaginal matrix ring containing dapivirine for the prevention of HIV-1 infection in women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 8, 2012. NLM Identifier: NCT01617096. https://clinicaltrials.gov/ct2/show/NCT01617096. Accessed June 1, 2021
  16. Nel A, van Niekerk N, Kapiga S, et al. Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. N Engl J Med. 2016;375(22):2133-2143. doi:10.1056/NEJMoa1602046
  17. Penrose K, Goetz BJ, Gordon KC, et al. Does the E138A mutation in ASPIRE seroconverters affect susceptibility to dapivirine? Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, WA. Abstract 951. http://www.croiconference.org/sessions/does-e138a-mutation-aspire-seroconverters-affect-susceptibility-dapivirine. Accessed June 1, 2021
  18. Riddler S, Balkus J, Mellors J, et al. NNRTI-containing ART is effective for dapivirine ring breakthrough HIV-1 infection. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, WA. Abstract 952. http://www.croiconference.org/sessions/nnrti-containing-art-effective-dapivirine-ring-breakthrough-hiv-1-infection. Accessed June 1, 2021
  19. Rosenberg Z. Dapivirine ring: the roadmap to licensure. Slides presented at: MTN Regional Meeting; October 4-8, 2015; Cape Town, South Africa. http://www.mtnstopshiv.org/sites/default/files/attachments/ROSENBERG2015-10-MTN-regional-mtg-Zeda_draftSept29.pdf. Accessed June 1, 2021
  20. International Partnership for Microbicides, Inc. A follow-on, open-label trial to assess continued safety of and adherence to the dapivirine (25 mg) vaginal Ring-004 in healthy, HIV-negative women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 25, 2016. NLM Identifier: NCT02862171. https://clinicaltrials.gov/ct2/show/NCT02862171. Accessed June 1, 2021
  21. International Partnership for Microbicides, Inc. A Phase 3B open-label follow-on trial to assess the continued safety of and adherence to a vaginal ring containing dapivirine in women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 18, 2016. NLM Identifier: NCT02858037. https://clinicaltrials.gov/ct2/show/NCT02858037. Accessed June 1, 2021
  22. International Partnership for Microbicides (IPM) website. Clinical trials. https://www.ipmglobal.org/our-work/research/clinical-trial. Accessed June 1, 2021
  23. International Partnership for Microbicides, Inc. A Phase 1, randomized pharmacokinetics and safety study of extended duration dapivirine vaginal rings. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 25, 2017. NLM Identifier: NCT03234400. https://clinicaltrials.gov/ct2/show/NCT03234400. Accessed June 1, 2021
  24. International Partnership for Microbicides, Inc. A randomized, Phase 1, open-label study in healthy HIV-negative women to evaluate the pharmacokinetics, safety and bleeding patterns associated with 90-day use of matrix vaginal rings containing 200 mg dapivirine and 320 mg levonorgestrel. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 9, 2018. NLM Identifier: NCT03467347. https://clinicaltrials.gov/ct2/show/NCT03467347. Accessed June 1, 2021
  25. National Institute of Allergy and Infectious Diseases (NIAID). A Phase 2a crossover trial evaluating the safety of and adherence to a vaginal matrix ring containing dapivirine and oral emtricitabine/tenofovir disoproxil fumarate in an adolescent and young adult female population. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 10, 2018. NLM Identifier: NCT03593655. https://clinicaltrials.gov/ct2/show/NCT03593655. Accessed June 1, 2021
  26. Microbicide Trials Network (MTN) website. About the REACH Study (MTN-034). https://mtnstopshiv.org/news/about-reach-study-mtn-034. Accessed June 1, 2021
  27. National Institute of Allergy and Infectious Diseases (NIAID). Phase 3b, randomized, open label safety trial of dapivirine vaginal ring and oral Truvada® use in pregnancy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 24, 2019. NLM Identifier: NCT03965923. https://clinicaltrials.gov/ct2/show/NCT03965923. Accessed June 1, 2021
  28. National Institute of Allergy and Infectious Diseases (NIAID). Phase 3B, randomized, open-label, safety, and drug detection study of dapivirine vaginal ring and oral Truvada® in breastfeeding mother-infant pairs. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 24, 2019. NLM Identifier: NCT04140266. https://clinicaltrials.gov/ct2/show/NCT04140266. Accessed June 1, 2021
  29. International Partnership for Microbicides (IPM) website. Darunavir. https://www.ipmglobal.org/our-work/arvs-in-the-pipeline/darunavir. Accessed June 1, 2021
  30. National Institute of Allergy and Infectious Diseases (NIAID). An Open Label Randomized Phase 1 Pharmacokinetic Study of Dapivirine Gel Administered Rectally to HIV-1 Seronegative Adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 2, 2018. NLM Identifier: NCT03393468. https://clinicaltrials.gov/ct2/show/NCT03393468. Accessed June 1, 2021
  31. Nel A, Niekerk N van, Baelen BV, et al. Safety, adherence, and HIV-1 seroconversion among women using the dapivirine vaginal ring (DREAM): an open-label, extension study. The Lancet HIV. 2021;8(2):e77-e86. doi:10.1016/S2352-3018(20)30300-3
  32. Baeten JM, Palanee-Phillips T, Brown ER, et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med. 2016;375(22):2121-2132. doi:10.1056/NEJMoa1506110
  33. Baeten J, Palanee-Phillips T, Mgodi N, et al. High uptake and sustained impact on HIV-1 incidence: final results of an open-label extension trial of the dapivirine ring. Slides presented at: International AIDS Society (IAS) Conference on HIV Science; July 21-24, 2019; Mexico City, Mexico. https://programme.ias2019.org/PAGMaterial/PPT/1114_3329/MTN-025 HOPE - IAS 2019 presentation -- version20190718final.pptx. Accessed June 1, 2021
  34. Nel A, Haazen W, Russell M, Nuttall J, Van Niekerk N, Treijtel N. Drug-drug Interactions between the Dapivirine Vaginal Ring (Ring-004) and Miconazole Nitrate Vaginal Capsule (Gyno-Daktarin®). AIDS Research and Human Retroviruses. 2014;30(S1):A144-A144. doi:10.1089/aid.2014.5291.abstract
  35. Balkus J, Palanee-Phillips T, Siva S, et al. Dapivirine ring use does not diminish the effectiveness of hormonal contraception. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13–16, 2017; Seattle, WA. Abstract 88. http://www.croiconference.org/sessions/dapivirine-ring-use-does-not-diminish-effectiveness-hormonal-contraception. Accessed June 1, 2021

Last Reviewed: June 1, 2021