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Investigational

Dapivirine  Audio icon

Other Names: DAP, Ring-004, TMC-120, dapivirine IVR, dapivirine intravaginal ring
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
Company: Janssen Research and Development, LLC; International Partnership for Microbicides (IPM)
Phase of Development: Phase III (Dapivirine intravaginal ring [IVR] is in Phase III testing. Other dapivirine-based microbicide products are in earlier phases of study.)
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Chemical Image:
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dapivirine
dapivirine
Molecular Weight: 329.405

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

Patent Version Content

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 the infection process 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

In a pharmacokinetic and safety study of two formulations of dapivirine vaginal gel (0.05%) applied once daily over 11 days, plasma concentrations of dapivirine did not exceed 1.1 ng/mL. Dapivirine cervicovaginal fluid concentrations were at least 5 logs greater than dapivirine’s in vitro inhibitory concentrations for wild type HIV-1 virus.8,11

One study evaluated Ring-004, which is a dapivirine silicone elastomer matrix intravaginal ring (IVR) containing 25 mg dapivirine. Ring-004 was used over 28 consecutive days in HIV-uninfected women. Dapivirine vaginal fluid concentrations were found to be highest near the location of the ring, followed by the cervix and introitus. Day 28 dapivirine concentrations in vaginal fluid at all three collection sites were more than 3900-fold the 99% inhibitory concentration (IC99) for dapivirine in a tissue explant infection model, while dapivirine plasma concentrations were low (less than 1 ng/mL).12,13

Another study evaluated Ring-004 worn continuously for different periods of time, with the longest period of time lasting 12 weeks. When the IVR was worn for more than 4 weeks at a time, there was a decline both in dapivirine ring residual levels and in dapivirine plasma and vaginal fluid concentrations. Mean vaginal fluid concentrations at the end of 12 weeks of continuous IVR use were more than 4000-times above the in vitro IC99 in cervical tissue.14

Half-life (T½): In a study of two formulations of dapivirine vaginal gel (0.05%) used once daily over 11 days, the dapivirine terminal half-life was 72 to 73 hours in plasma and 15 to 17 hours in vaginal fluids.11 In a study of dapivirine matrix and reservoir IVRs, the estimated terminal half-life for dapivirine in plasma after IVR removal on day 28 was 64 hours for the matrix IVR and 83 hours for the reservoir IVR; the estimated terminal half-life for dapivirine in vaginal fluids after IVR removal was 15 to 16 hours for both IVR types.15

Metabolism/Elimination: Cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes were found locally expressed in vaginal and colorectal tissues and may have a role in the metabolism of dapivirine in these tissue compartments.16

Resistance: In an in vitro study, primary cells were infected with HIV-1 of varying subtypes and resistance profiles and then exposed to increasing, suboptimal concentrations of dapivirine, tenofovir, or dapivirine in combination with tenofovir. Results indicated that suboptimal doses of dapivirine alone permitted the emergence of more reverse transcriptase mutations than did suboptimal doses of dapivirine in combination with tenofovir or tenofovir alone. Suboptimal concentrations of tenofovir alone resulted in the development of one NRTI mutation, K65R. In this study, the drug-resistant virus selected with suboptimal doses of dapivirine in combination with tenofovir demonstrated resistance to nevirapine, but it remained susceptible to lamivudine and stavudine.17

Another study investigated dapivirine cross-resistance among recombinant viruses in residual plasma samples derived from HIV-1 subtype C-infected individuals failing first-line neviripine- or efavirenz-containing antiretroviral therapy (ART) regimens in South Africa. In this study, 78% (47 out of 60) of virus samples from individuals failing neviripine- or efavirenz-containing treatment exhibited ≥10-fold resistance to dapivirine when compared to treatment-naive samples (based on 50% inhibitory concentration [IC50] values). The median dapivirine 90% inhibitory concentration (IC90) of viruses with ≥3-fold resistance to dapivirine exceeded maximum dapivirine plasma concentrations during 1 month of IVR use (maximum plasma concentrations were based on published data). However, dapivirine vaginal fluid concentrations after 28 days of IVR use (vaginal fluid concentrations were based on published data) were 900-times higher than the median IC90 of viruses with ≥10-fold dapivirine resistance. Investigators concluded that high genital tract dapivirine concentrations from dapivirine IVR use may be sufficient to block both wild type and resistant virus.18

Results from two Phase III safety/efficacy studies (The Ring Study and ASPIRE) found no evidence that use of the dapivirine IVR increased ARV-resistant HIV among participants who acquired HIV.19,20


Clinical Trials



Study Identifiers: IPM 027 (The Ring Study)21; NCT0153922622
Phase: III
Study Purpose: Study to evaluate the safety and effectiveness of a dapivirine silicone elastomer matrix IVR (Ring-004) for the prevention of HIV infection in women
Study Population: HIV-uninfected, sexually active women who are 18 to 45 years of age and located in South Africa and Uganda
Dosing: Dapivirine 25-mg IVR versus placebo IVR, both inserted once every 4 weeks over a period of 24 months.19,21,22
* On the basis of an independent Data Safety Monitoring Board (DSMB) recommendation, final safety and efficacy analyses for The Ring Study were performed prior to the planned study completion date.19,21 An open-label extension study (DREAM) is planned to take place. The extension study will provide the dapivirine ring to eligible Ring Study participants and will help to answer critical questions about the product.23

(See references cited above for information on study results.)


Study Identifiers: MTN-020 (ASPIRE); NCT0161709624
Phase: III
Study Purpose: Study to evaluate the safety and effectiveness of a dapivirine silicone elastomer matrix IVR (Ring-004) for the prevention of HIV infection in women
Study Population: HIV-uninfected, sexually active women who are 18 to 45 years of age and located in Malawi, South Africa, Uganda, and Zimbabwe
Dosing: Dapivirine 25-mg IVR versus placebo IVR, both inserted once monthly over a period of at least 12 months.19,20,24-27
* An open-label extension study (HOPE) is planned to take place. The extension study will provide the dapivirine ring to eligible ASPIRE study participants and will gather additional product safety and participant adherence data.28

(See references cited above for information on study results.)

Additional studies of dapivirine IVR have been completed or are ongoing or planned. These include the following: 1) Phase IIa dapivirine IVR studies in postmenopausal women and in adolescent females; 2) a Phase I study of a combination IVR containing dapivirine and maraviroc; 3) Phase II dapivirine vaginal gel studies; 4) a Phase I study of a combination vaginal gel containing dapivirine and darunavir; and 5) Phase I dapivirine vaginal film studies.4,8,29-32


Adverse Events


In both Phase III studies (The Ring Study and ASPIRE), dapivirine IVR use in women was reported to be safe, with a similar rate of adverse events in both the active drug and placebo arms. Among participants who acquired HIV in either study, there was no evidence that use of the dapivirine IVR increased ARV-resistant HIV.19-21,25 In The Ring Study, adverse events related to dapivirine IVR included metrorrhagia, menometrorrhagia, pelvic discomfort/pain, suprapubic pain, and application site pain.21


Drug Interactions


A drug-drug interaction study between dapivirine IVR (Ring-004) and miconazole nitrate (1200-mg vaginal capsule) found that concomitant use altered local and systemic levels of both drugs; however, the observed changes were considered unlikely to adversely affect the efficacy of either drug.33


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/244767-67-7. Last accessed on March 11, 2016.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on March 11, 2016.
  3. International Partnership for Microbicides (IPM): Press Release, dated May 8, 2014. IPM Receives Worldwide Rights to HIV Prevention Medicine. Available at: http://ipmglobal.org/publications/ipm-receives-worldwide-rights-hiv-prevention-medicine. Last accessed on March 11, 2016.
  4. International Partnership for Microbicides (IPM) website. Our Products. Available at: http://www.ipmglobal.org/our-work/our-products. Last accessed on March 11, 2016.
  5. National Institute of Allergy and Infectious Diseases (NIAID). NIAID Research on Microbicides. Available at: http://www.niaid.nih.gov/topics/hivaids/research/prevention/pages/topicalmicrobicides.aspx. Last accessed on March 11, 2016.
  6. Shattock RJ, Rosenberg Z. Microbicides: Topical Prevention against HIV. 2012 Feb; 2(2): a007385. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281595/. Last accessed on March 11, 2016.
  7. Balzarini J, Van Damme L. Intravaginal and intrarectal microbicides to prevent HIV infection. CMAJ. 2005 Feb 15; 172(4): 461-4. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC548403/. Last accessed on March 11, 2016.
  8. Adams JL, Kashuba AD. Formulation, pharmacokinetics and pharmacodynamics of topical microbicides. Best Pract Res Clin Obstet Gynaecol. 2012 Aug; 26(4): 451-62. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662244/. Last accessed on March 11, 2016.
  9. Garg AB, Nuttall J, Romano J. The future of HIV microbicides: challenges and opportunities. Antivir Chem Chemother. 2009; 19(4): 143-50. Available at: http://www.intmedpress.com/servefile.cfm?suid=a04ed6be-7c85-4bc7-9f9d-b9f5e9290a52. Last accessed on March 11, 2016.
  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 Mar; 52(3): 909-14. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258487/. Last accessed on March 11, 2016.
  11. Nel AM, Smythe SC, Habibi S, Kaptur PE, Romano JW. Pharmacokinetics of 2 dapivirine vaginal microbicide gels and their safety vs. Hydroxyethyl cellulose-based universal placebo gel. J Acquir Immune Defic Syndr. 2010 Oct; 55(2): 161-9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20574411. Last accessed on March 11, 2016.
  12. Nel A, Haazen W, Nuttall J, Romano J, Rosenberg Z, van Niekerk N. A safety and pharmacokinetic trial assessing delivery of dapivirine from a vaginal ring in healthy women. AIDS. 2014 Jun 19; 28(10): 1479-87. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24901365. Last accessed on March 11, 2016.
  13. International Partnership for Microbicides. IPM Clinical Trials. Available at: http://www.ipmglobal.org/sites/default/files/Clinical_Trials_Fact_Sheet_OCT-14.pdf. Last accessed on March 11, 2016.
  14. Nel AM, Haazen W, Russell M, Nuttall JP, Van Niekerk N, Treijtel N. Local and Systemic Pharmacokinetic Profile of Dapivirine Vaginal Ring-004 When Used Continuously Over Various Periods up to Twelve Weeks. Abstract presented at: 22nd Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, Washington. Abstract 524. Available at: http://www.croiconference.org/sites/default/files/uploads/croi2015-program-abstracts.pdf. Last accessed on March 11, 2016.
  15. Nel A, Smythe S, Young K, et al. Safety and Pharmacokinetics of Dapivirine Delivery From Matrix and Reservoir Intravaginal Rings to HIV-Negative Women. J Acquir Immune Defic Syndr. 2009 Aug 1; 51(4): 416-23. Available at: http://journals.lww.com/jaids/Fulltext/2009/08010/Safety_and_Pharmacokinetics_of_Dapivirine_Delivery.7.aspx. Last accessed on March 11, 2016.
  16. To EE, Hendrix CW, Bumpus NN. Dissimilarities in the Metabolism of Antiretroviral Drugs used in HIV Pre-exposure Prophylaxis in Colon and Vagina Tissues. Biochem Pharmacol. 2013 Oct 1; 86(7): 979-90. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807636/. Last accessed on March 11, 2016.
  17. Schader SM, Oliveira M, Ibanescu RI, Moisi D, Colby-Germinario SP, Wainberg MA. In Vitro Resistance Profile of the Candidate HIV-1 Microbicide Drug Dapivirine. Antimicrob Agents Chemother. 2012 Feb; 56(2): 751-6. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264246/. Last accessed on March 11, 2016.
  18. Penrose KJ, Hamanishi KA, Gordon KC, et al. Frequent Dapivirine Cross-Resistance of HIV from 1st-line ART Failures in S. Africa. Abstract presented at: 22nd Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, Washington. Abstract 985. Available at: http://www.croiconference.org/sites/default/files/uploads/croi2015-program-abstracts.pdf. Last accessed on March 11, 2016.
  19. 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. Available at: http://www.ipmglobal.org/publications/two-large-studies-show-ipm%E2%80%99s-monthly-vaginal-ring-helps-protect-women-against-hiv. Last accessed on March 11, 2016.
  20. 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. February 22, 2016; DOI: 10.1056/NEJMoa1506110. Available at: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1506110. Last accessed on March 11, 2016.
  21. Nel A, Kapiga S, Bekker LG, Devlin B, Borremans M, Rosenberg Z. Safety and Efficacy of Dapivirine Vaginal Ring for HIV-1 Prevention in African Women. Abstract presented at: 23rd Conference on Retroviruses and Opportunistic Infections (CROI); February 22 – 25, 2016; Boston, MA. Abstract 110LB. Available at: http://www.croiconference.org/sessions/safety-and-efficacy-dapivirine-vaginal-ring-hiv-1-prevention-african-women. Last accessed on March 11, 2016.
  22. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01539226. Last accessed on March 11, 2016.
  23. International Partnership for Microbicides website. Phase III Results: Frequently Asked Questions. Available at: http://ipmglobal.org/our-work/our-products/dapivirine-ring/phase-iii-results/frequently-asked-questions. Last accessed on March 16, 2016.
  24. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01617096. Last accessed on March 11, 2016.
  25. Baeten JM, Palanee-Phillips T, Brown ER, et al. A Phase III Trial of the Dapivirine Vaginal Ring for HIV-1 Prevention in Women. Abstract presented at: 23rd Conference on Retroviruses and Opportunistic Infections (CROI); February 22 – 25, 2016; Boston, MA. Abstract 109LB. Available at: http://www.croiconference.org/sessions/phase-iii-trial-dapivirine-vaginal-ring-hiv-1-prevention-women. Last accessed on March 11, 2016.
  26. National Institute of Allergy and Infectious Diseases (NIAID): News Release, dated February 22, 2016. Vaginal Ring Provides Partial Protection from HIV in Large Multinational Trial. Available at: http://www.niaid.nih.gov/news/newsreleases/2016/Pages/ASPIRE.aspx. Last accessed on March 11, 2016.
  27. Microbicide Trials Network (MTN): Press Release, dated February 22, 2016. Dapivirine vaginal ring helped protect women against HIV in ASPIRE Phase III trial. Available at: http://www.mtnstopshiv.org/node/7229. Last accessed on March 11, 2016.
  28. National Institute of Allergy and Infectious Diseases (NIAID): News Release, dated March 13, 2016. NIAID to Fund Further Study of Dapivirine Vaginal Ring for HIV Prevention. Available at: http://www.niaid.nih.gov/news/newsreleases/2016/Pages/HOPE-trial.aspx. Last accessed on March 14, 2016.
  29. Chen BA, Hoesley C, Salata RA, et al. Safety and Pharmacokinetics of Dapivirine Vaginal Rings in Postmenopausal US Women. Abstract presented at: 23rd Conference on Retroviruses and Opportunistic Infections (CROI); February 22 – 25, 2016; Boston, MA. Abstract 872. Available at: http://www.croiconference.org/sessions/safety-and-pharmacokinetics-dapivirine-vaginal-rings-postmenopausal-us-women. Last accessed on March 11, 2016.
  30. International Partnership for Microbicides, Inc. Phae 2A Study of a Vaginal Ring Containing Dapivirine in Adolescent Females. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 2, 2014. NLM Identifier: NCT02028338. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02028338. Last accessed on March 11, 2016.
  31. Chen BA, Panther L, Marzinke MA, et al. Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings: A Double-Blind Randomized Trial. J Acquir Immune Defic Syndr. 2015 Nov 1; 70(3): 242-9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26034880. Last accessed on March 11, 2016.
  32. Bunge KE, Dezzutti CS, Rohan LC, et al. A Phase 1 trial to assess the safety, acceptability, pharmacokinetics and pharmacodynamics of a novel dapivirine vaginal film. J Acquir Immune Defic Syndr. 2015 Nov 11. [Epub ahead of print]. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26565716. Last accessed on March 11, 2016.
  33. 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 (GynoDaktarin®). Poster presented at: HIV Research for Prevention 2014: AIDS Vaccine, Microbicide and ARV-based Prevention Science (HIVR4P); October 28-31, 2014; Cape Town, South Africa. Poster P15.09. Available at: http://hivr4p.org/abstracts-and-conference-materials?download=191:complete-abstract-book. Last accessed on March 11, 2016.


Last Reviewed: March 16, 2016

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