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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.)
Chemical Image:
Click image to enlarge
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's Next Generation Products presentation4)
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 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 


Dosing in Clinical Trials


Study Identifiers: IPM 015; NCT0107117419
Phase: I/II
Study Purpose: Study to evaluate the safety and acceptability of a dapivirine silicone elastomer matrix IVR (Ring-004)
Study Population: HIV-uninfected women in Kenya, Malawi, South Africa, and Tanzania
Dosing: Dapivirine 25-mg IVR versus placebo IVR, both inserted once every 28 days over 12 weeks (3 rings total).19,20
(See references cited above for information on study results.)

Study Identifiers: IPM 027 (The Ring Study)21; NCT0153922622
Phase: II/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 women 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.21-23

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 women 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.21,23,24

 
Additional studies of dapivirine IVR have been completed or are ongoing or planned, including a Phase I study of a combination IVR containing dapivirine and maraviroc. Vaginal gel and film formulations of dapivirine have also been studied in early-phase clinical trials.8,25,26


Adverse Events


In the Phase I/II IPM 015 study that compared dapivirine 25-mg vaginal ring inserted once every 28 days versus placebo over a 12-week period, adverse events were similar in both arms. Five serious adverse events occurred, all of which were unrelated to dapivirine use. No adverse events occurred that were definitely related to dapivirine. There were no cases of non-serious adverse events leading to ring discontinuations.20


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.27


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 31, 2015.
  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 31, 2015.
  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 31, 2015.
  4. Rosenberg Z. IPM’s Next Generation Products. Slides presented at: Microbicide Trials Network (MTN) 2014 Annual Meeting; February 23-26, 2014; Bethesda, Maryland. Available at: http://www.mtnstopshiv.org/sites/default/files/attachments/ROSENBERG-MTNPlenary_Z%20Rosenberg-24FEB14.pdf. Last accessed on March 31, 2015.
  5. National Institute of Allergy and Infectious Diseases (NIAID). Topical Microbicides. Available at: http://www.niaid.nih.gov/topics/hivaids/research/prevention/pages/topicalmicrobicides.aspx. Last accessed on March 31, 2015.
  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 31, 2015.
  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 31, 2015.
  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 31, 2015.
  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 31, 2015.
  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 31, 2015.
  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 31, 2015.
  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 31, 2015.
  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 31, 2015.
  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 31, 2015.
  15. Nel A, Smythe S, Young K, et al. Safety and Pharmacokinetics of Dapivirine Delivery From Matrix and RIntravaginal 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 31, 2015.
  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 31, 2015.
  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 31, 2015.
  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 31, 2015.
  19. International Partnership for Microbicides, Inc. A Double-Blind, Randomized, Placebo-Controlled Phase I/II Study to Evaluate the Safety of an Intravaginal Matrix Ring With Dapivirine in Healthy, HIV-Negative Women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 17, 2010. NLM Identifier: NCT01071174. Available at:  https://www.clinicaltrials.gov/ct2/show/NCT01071174. Last accessed on March 31, 2015.
  20. Nel A, Kamupira M, Woodsong C, et al. Safety, Acceptibility and Pharmacokinetic Assessment (Adherence) of Monthly Dapivirine Vaginal Microbicide Rings (Ring-004) for HIV Prevention. 19th Conference on Retroviruses and Opportunistic Infections (CROI); March 5-8, 2012; Seattle, WA. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2012. Available at: http://www.natap.org/2012/CROI/croi_160.htm. Last accessed on March 31, 2015.
  21. Nel A. The Path to Licensure for the Dapivirine Ring. Slides presented at: Microbicide Trials Network (MTN) 2014 Regional Meeting; October 24-26, 2014; Cape Town, South Africa. Available at: http://www.mtnstopshiv.org/sites/default/files/attachments/NEL-14Oct25_MTN%20Plenary_The%20Path%20to%20Lisensure%20for%20the%20Dapivirine%20Ring.pdf. Last accessed on March 31, 2015.
  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 31, 2015.
  23. International Partnership for Microbicides (IPM) website. Two Phase III Sister Studies of a Microbicide Ring to Prevent HIV: The Ring Study & ASPIRE. Available at: http://www.ipmglobal.org/node/668. Last accessed on March 31, 2015.
  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 31, 2015.
  25. Bunge KE, Dezzutti CS, Macio I, et al. FAME-02: A Phase I Trial To Assess Safety, PK, and PD of Gel and Film Formulations of Dapivirine. Abstract presented at: 21st Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, Massachusetts. Abstract 42LB. Available at: http://croi2014.org/sites/default/files/uploads/CROI2014_Final_Abstracts.pdf. Last accessed on March 31, 2015.
  26. Chen BA, Panther L, Hoesley C, et al. Safety and Pharmacokinetics/Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings. Abstract presented at: 21st Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, Massachusetts. Abstract 41. Available at: http://croi2014.org/sites/default/files/uploads/CROI2014_Final_Abstracts.pdf. Last accessed on March 31, 2015.
  27. 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 31, 2015.
 


Last Reviewed: March 31, 2015

Last Updated: March 31, 2015


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