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Drugs

Dapivirine

Other Names: DAP, DPV, 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 Organization: Janssen Research and Development, LLC; International Partnership for Microbicides (IPM) Phase of Development: The dapivirine intravaginal ring is in Phase IIIb testing. Other dapivirine-based microbicide products are in earlier phases of study.

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)

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

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

Half-life (T½): In a study of 2 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, dapivirine half-life was measured in women after IVR removal following 28 consecutive days of use. The estimated terminal half-life for dapivirine was 64 hours (plasma) and 15 to 16 hours (vaginal fluids) with the matrix IVR, and it was 83 hours (plasma) and 15 to 16 hours (vaginal fluids) with the reservoir IVR.12

Metabolism/Elimination: CYP and UGT enzymes have been found to be locally expressed in vaginal and colorectal tissues and may have a role in the metabolism of dapivirine in these tissue compartments.13

Resistance: In vitro, dapivirine has demonstrated reduced antiviral activity against subtype B virus with certain single NNRTI mutations. Low-level resistance to dapivirine occurred with virus containing K101E, K103N, or Y181C, 3 commonly transmitted NNRTI resistance mutations. Additionally, low-level resistance was seen with the E138K, F227C, and K103S mutations. Intermediate- or high-level dapivirine resistance was conferred by the L100V, L100I, M230L, Y188L, K101P, Y181I, and Y181V mutations.14,15 

Dapivirine cross-resistance was also evaluated using plasma samples derived from HIV-1 subtype C-infected individuals failing first-line neviripine- or efavirenz-containing ART regimens in South Africa. The majority of virus samples demonstrated cross-resistance to dapivirine. Although resistance levels (based on required inhibitory concentrations of dapivirine) were found to be greater than the expected plasma concentrations of dapivirine during ring use, researchers concluded that both wild type and resistant virus may be inhibited by high genital tract dapivirine concentrations.16,17

In the context of suboptimal use of microbicides, the effects of suboptimal concentrations of dapivirine, tenofovir, or dapivirine plus tenofovir were examined in vitro. Suboptimal doses of dapivirine alone permitted the emergence of more reverse transcriptase mutations than did suboptimal doses of dapivirine plus tenofovir or tenofovir alone. Suboptimal concentrations of tenofovir alone resulted in the development of 1 NRTI mutation, K65R. Drug-resistant virus selected with suboptimal doses of dapivirine plus tenofovir demonstrated resistance to nevirapine, but it remained susceptible to lamivudine and stavudine.18

Results from 2 Phase III 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.19-21 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.22 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.23,24

 


Clinical Trials


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 is a Phase III trial, and the DREAM study is a Phase IIIb trial. 
Study Purpose: The Ring 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. The DREAM study is an ongoing open-label follow-on study to continue evaluating dapivirine safety and participant adherence in women who were enrolled in the Ring study.
Study Population:

  • Participants in the Ring study were HIV-uninfected, sexually active women who were 18 to 45 years of age and located in South Africa and Uganda.
  • Participants in the ongoing DREAM study are HIV-uninfected women who participated in the Ring study. 

Dosing:

  • Ring study: Participants received either dapivirine 25-mg IVR or placebo IVR, both replaced once every 4 weeks for up to 24 months. (Final safety and efficacy analyses for the Ring study were performed prior to the planned study completion date.)
    * The Ring study has been completed.
  • DREAM study: Participants will receive dapivirine 25-mg IVR that will be replaced once every 4 weeks. Participants will be assigned to either 1 clinic visit every month or 1 clinic visit every 3 months. The study is planned for at least 1 year.19,20,22,25-28 

* The DREAM study is ongoing.

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 is a Phase III trial, and HOPE is a Phase IIIb trial.
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 is an ongoing open-label follow-on study to continue evaluating dapivirine safety and participant adherence in women who were enrolled in ASPIRE.
Study Population:

  • Participants in the ASPIRE study were HIV-uninfected, sexually active women who were 18 to 45 years of age and located in Malawi, South Africa, Uganda, and Zimbabwe.
  • Participants in the ongoing HOPE study are HIV-uninfected women who participated in ASPIRE.

Dosing:

  • ASPIRE study: Participants received either dapivirine 25-mg IVR or placebo IVR, both replaced once monthly over a period of at least 12 months.
    * ASPIRE has been completed.
  • HOPE study: Participants will receive dapivirine 25-mg IVR that will be replaced once every 4 weeks. Participants will be assigned to either 1 clinic visit every month or 1 clinic visit every 3 months. The study is planned for at least 1 year.21,27,29-34
    * The HOPE study is ongoing.
     

Selected Study Results:


Additional dapivirine-based IVR studies have also been completed or are ongoing or planned.35 These include (1) REACH (NCT03074786), a Phase IIa crossover study in females16 to 21 years of age that will evaluate product safety and participant adherence to dapivirine IVR and oral emtricitabine/tenofovir DF, (2) MTN-030/IPM 041 (NCT02855346), a Phase I pharmacokinetic and safety study that will assess a combination IVR containing dapivirine plus levonorgestrel, and (3) MTN-013/IPM 026 (NCT01363037), a Phase I study that evaluated a combination IVR containing dapivirine and maraviroc.36-39

Other dapivirine-based microbicide formulations are also in clinical development, such as a vaginal gel (Phase II) and a vaginal film (Phase I). A combination vaginal gel containing dapivirine and darunavir is also in early stages of study.4,40

 


Adverse Events


In both Phase III studies (Ring study; NCT01539226 and ASPIRE study; NCT01617096), 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.19,22,32 In both studies, no dapivirine-related serious adverse events (SAEs) or Grade 3 or 4 AEs occurred. In the Ring study, AEs related to dapivirine IVR included metrorrhagia, pelvic discomfort/pain, suprapubic pain, and application site pain, all of which were mild in severity. In ASPIRE, dapivirine-related AEs included moderate cervivitis, urinary tract infection, headache, urinary incontinence, cervix erythema and oedema, dyspareunia, and pelvic pain.22,32   


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.41

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.42


References


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Last Reviewed: April 7, 2017