Drugs

Maraviroc (HIV prevention)

Other Names: MVC (HIV prevention), Selzentry (HIV prevention) Drug Class: CCR5 Antagonist
Molecular Formula: C29 H41 FNO
Registry Number: 376348-65-1 (CAS) Chemical Name: Cyclohexanecarboxamide, 4,4-difluoro-N-((1S)-3-((3-exo)-3-(3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl)-8-azabicyclo(3.2.1)oct-8-yl)-1-phenylpropyl)- Chemical Class: Phenylpropylamines Organization: ViiV Healthcare Phase of Development: Oral maraviroc for use as HIV pre-exposure prophylaxis is in Phase II development. (Topical microbicide formulations of maraviroc are in Phase I development.) 

Chemical Image:

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maraviroc

maraviroc

Molecular Weight: 513.6729

(Compound details obtained from ChemIDplus Advanced,1 Antimicrobial Agents and Chemotherapy article,2 Selzentry Full Prescribing Information,3 Treatment Action Group 2017 Pipeline Report,4 and ClinicalTrials.gov5,6)

Pharmacology


Mechanism of Action: HIV-1 CCR5 antagonist. Maraviroc is a slowly reversible, small molecule CCR5 co-receptor antagonist that prevents viral entry by selectively binding to the CCR5 human chemokine receptor and subsequently inhibiting the interaction between HIV-1 gp120 and CCR5.3

Maraviroc is an FDA-approved treatment for HIV infection in adults with only CCR5-tropic HIV-1.3 Because some studies have demonstrated that oral maraviroc is rapidly absorbed and achieves high concentrations in cervicovaginal and rectal tissues, oral maraviroc has been evaluated as an agent for HIV pre-exposure prophylaxis (PrEP).5,7-9 Topical microbicide formulations containing maraviroc (intravaginal ring [IVR] and gel) are in Phase I development for HIV prevention.4,10

Half-life (T½): After oral dosing to steady state in healthy participants, the terminal elimination half-life of maraviroc in plasma was 14 to 18 hours.3 The elimination half-life of orally dosed maraviroc in plasma and in mucosal tissue compartments has been described and compared to oral tenofovir DF in a humanized mouse model. In humanized mice, the maraviroc half-life was 1 hour in plasma, 2.6 hours in vaginal tissue, 1.5 hours in rectal tissue, and 1.2 hours in intestinal tissue. When compared with the half-lives of tenofovir DF and its active metabolite (TFV-DP), the maraviroc half-life in tissue compartments was much shorter.11

Metabolism/Elimination: Maraviroc is metabolized in the liver by CYP enzymes, primarily CYP3A, to inactive metabolites. Following a single oral 300-mg dose of radiolabeled maraviroc, unchanged maraviroc is the major circulating component in plasma, accounting for approximately 42% of radioactivity. The major circulating metabolite, accounting for approximately 22% of radioactivity, is a secondary amine formed by N-dealkylation; it has no important pharmacological activity.3

Following a single 300-mg dose of radiolabeled maraviroc, approximately 20% of radioactivity is recovered in the urine and 76% is recovered in the feces over 168 hours. Unchanged maraviroc is the major component excreted in both urine (8% of dose) and feces (25% of dose).3

Resistance: Drug resistance to maraviroc is uncommon, and virologic failure while on a maraviroc-containing regimen is usually associated with the emergence of dual-tropic HIV instead of drug-resistant HIV strains.12,13 Development of drug resistance to maraviroc in HIV prevention studies has not been described to occur. In the Phase II HPTN 069/A5305 safety/tolerability study (NCT01505114), 406 men who have sex with men (MSM) and 188 women, all of whom did not have HIV but were at-risk for acquiring HIV, were assigned to one of three maraviroc-containing regimens or to emtricitabine plus tenofovir DF for 48 weeks. Five men taking maraviroc became infected with R5 HIV and none had genotypic resistance.5,13,14 There were no new HIV infections in the cohort of at-risk women.14

Maraviroc resistance in cell-culture studies and clinical resistance to maraviroc in in vivo HIV treatment studies are described in the FDA-approved Full Prescribing Information for Selzentry.3


Select Clinical Trials


Oral Maraviroc for HIV Prevention

Study Identifiers: HPTN 069/A5305 (NEXT PrEP); NCT01505114
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: II
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the safety and tolerability of four different ARV regimens for HIV PrEP.
Study Population: Participants were MSM at risk for acquiring HIV infection and women at risk for acquiring HIV infection.5
Selected Study Results:

Other HIV prevention studies evaluating oral maraviroc have been completed, including:

  • MVC-PrEP (NCT01749566), a Phase I study that evaluated maraviroc concentrations in the blood and genital tract of women without HIV.15
  • MARAVIPREX (NCT01719627), a Phase I study that evaluated whether single-dose maraviroc could provide ex vivo protection against HIV infection in rectal mucosa samples from healthy men16
  •  A Phase IV study that assessed the ex vivo activity of single-dose maraviroc in rectal and vaginal tissue samples from healthy adults without HIV.17

Topical Microbicide Formulations of Maraviroc for HIV Prevention

Topical microbicide formulations containing maraviroc have been studied in Phase I trials. These formulations include 1) a maraviroc-only IVR, 2) a combination maraviroc/dapivirine IVR, 3) a combination tenofovir DF/emtricitabine/maraviroc IVR, and 4) a maraviroc gel administered rectally or vaginally.4,6,10,18


Adverse Events


HPTN 069/A5305 (NEXT PrEP) (NCT01505114):
In this Phase II study, analyses of the at-risk MSM and the at-risk women cohorts were done separately. Oral maraviroc-containing regimens were found to be comparably safe to oral emtricitabine plus tenofovir DF when used over 48 weeks in 406 randomized men and 188 randomized women. In the cohort of women, approximately one-third of the participants had discontinued study treatment by Week 48 for various reasons. In both cohorts, there were no differences by study arm in the proportion of participants who discontinued study drugs or time to study drug discontinuation.5,13,14,19

In the cohort of MSM, a total of 67 Grade 3-4 adverse events (AEs) occurred, but among the four study arms, there were no differences in occurrence or rate. Grade 2 or higher AEs that occurred in greater than 5% of participants included hypophosphatemia (17%) and upper respiratory tract infection (11%). Selected Grades 2-4 gastrointestinal (GI) and renal AEs that occurred included diarrhea, nausea, vomiting, unintentional weight loss, and increased creatinine; all of these were Grade 2 in severity.13 Increased gut-associated lymphoid tissue (GALT) T cell activation and increased HIV co-receptor (CCR5) expression was not observed in any of the study arms.20

In the cohort of at-risk women, 48 Grade 3-4 AEs occurred in 19% of participants, but there were no significant differences among the four study arms. Among the 48 Grade 3-4 AEs that occurred, 11 events were considered to be treatment-related. Selected Grades 2-4 GI and renal AEs that occurred included diarrhea, nausea, vomiting, unintentional weight loss, hypophosphatemia, and increased creatinine. The majority of these events were Grade 2 and all occurred at a similar rate across study groups. Two percent of participants had a sexually transmitted infection diagnosed during the study.14,19

Additional AEs known to be associated with maraviroc use are described in the FDA-approved Full Prescribing Information for Selzentry.3


Drug Interactions


In the HPTN 069/A5305 study (NCT01505114), no drug-drug interactions were noted with maraviroc, emtricitabine, and tenofovir DF.5,13

Maraviroc is a CYP3A and P-gp substrate, and its pharmacokinetics may potentially be altered by CYP3A and P-gp inhibitors and inducers. Dose adjustments may be required when maraviroc is coadministered with such drugs.3

In vitro data indicate that coadministered drugs metabolized by CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A are not likely to be inhibited by maraviroc. In addition, maraviroc is not a CYP1A2 inducer in vitro. Although in vitro results suggest that maraviroc could inhibit P-gp in the gut, an in vivo study with coadministered digoxin demonstrated that maraviroc may not inhibit or induce P-gp to a clinically significant degree.3

Detailed drug-drug interactions between maraviroc and coadministered drugs are described in the FDA-approved Full Prescribing Information for Selzentry.3


References


  1. United States National Library of Medicine. ChemIDplus Advanced: Maraviroc. https://chem.nlm.nih.gov/chemidplus/rn/376348-65-1. Accessed May 30, 2019
  2. Asin-Milan O, Sylla M, El-Far M, et al. Synergistic combinations of the CCR5 inhibitor VCH-286 with other classes of HIV-1 inhibitors. Antimicrob Agents Chemother. 2014;58(12):7565-7569.
  3. ViiV Healthcare Company. Selzentry: full prescribing information, November 2016. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=46f30ac5-c96b-429e-976d-8c5ee1c0761b. Accessed May 30, 2019
  4. Frick M, Gaudino A, Harrington M, et al. Treatment Action Group. 2017 pipeline report. http://www.pipelinereport.org/sites/default/files/2017%20Pipeline%20Report%20Final.pdf. Published July 2017. Accessed May 30, 2019
  5. National Institute of Allergy and Infectious Diseases (NIAID). A Phase II randomized, double-blind, study of the safety and tolerability of maraviroc (MVC), maraviroc + emtricitabine (MVC+FTC), maraviroc + tenofovir disoproxil fumarate (MVC+TDF), or tenofovir disoproxil fumarate + emtricitabine (TDF+FTC) for pre-exposure prophylaxis (PrEP) to prevent HIV transmission in at-risk men who have sex with men and in at-risk women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 4, 2012. NLM Identifier: NCT01505114. https://clinicaltrials.gov/ct2/show/NCT01505114. Accessed May 30, 2019
  6. International Partnership for Microbicides, Inc. CHARM-03: A randomized, open label, crossover Phase 1 safety and pharmacokinetic study of oral maraviroc and maraviroc 1% gel administered rectally and vaginally to HIV-1 seronegative adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 20, 2015. NLM Identifier: NCT02346084. https://clinicaltrials.gov/ct2/show/NCT02346084. Accessed May 30, 2019
  7. Brown KC, Patterson KB, Malone SA, et al. Single and multiple dose pharmacokinetics of maraviroc in saliva, semen, and rectal tissue of healthy HIV-negative men. J Infect Dis. 2011;203(10):1484-1490.
  8. Dumond JB, Patterson KB, Pecha AL, et al. Maraviroc concentrates in the cervicovaginal fluid and vaginal tissue of HIV-negative women. J Acquir Immune Defic Syndr 1999. 2009;51(5):546-553.
  9. Massud I, Aung W, Martin A, et al. Lack of prophylactic efficacy of oral maraviroc in macaques despite high drug concentrations in rectal tissues. J Virol. 2013;87(16):8952-8961.
  10. Auritec Pharmaceuticals. Open-label safety and pharmacokinetic study of single (TDF), dual (TDF-FTC), and triple ARV IVR (TDF-FTC-MVC) in healthy women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 4, 2014. NLM Identifier: NCT02431273. https://www.clinicaltrials.gov/ct2/show/NCT02431273. Accessed May 30, 2019
  11. Veselinovic M, Yang K-H, LeCureux J, et al. HIV pre-exposure prophylaxis: mucosal tissue drug distribution of RT inhibitor tenofovir and entry inhibitor maraviroc in a humanized mouse model. Virology. 2014;0:253-263.
  12. Abraham BK, Gulick R. Next generation oral PrEP: beyond tenofovir. Curr Opin HIV AIDS. 2012;7(6):600-606.
  13. Gulick R. HPTN 069 / ACTG A5305: Phase II study of maraviroc (MVC)-containing regimens for HIV PrEP in men who have sex with men (MSM). 23rd Conference on Retroviruses and Opportunistic Infections (CROI); February 22-25, 2016; Boston, MA. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2016. http://www.natap.org/2016/CROI/croi_39.htm. Accessed May 30, 2019
  14. Gulick RM. HPTN 069/ACTG A5305 Phase II study of maraviroc (MVC)-containing regimens for HIV PrEP in U.S. women. 21st International AIDS Conference (AIDS 2016); July 18-22, 2016; Durban, South Africa. Levin: HPTN 069 / ACTG A5305 Phase II Study of Maraviroc (MVC)-Containing Regimens for HIV PrEP in U.S. Women...."NO new infections....annual incidence rate 0%"; Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2016. http://www.natap.org/2016/IAC/IAC_15.htm. Accessed May 30, 2019
  15. Emory University. Exploring HIV entry blockade as a pre-exposure prophylaxis strategy in women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 9, 2012. NLM Identifier: NCT01749566. https://www.clinicaltrials.gov/ct2/show/NCT01749566. Accessed May 30, 2019
  16. Fundacio Lluita Contra la SIDA. Pilot study of protection against ex vivo HIV infection in rectal mucosa in health volunteers after administration of maraviroc. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 10, 2012. NLM Identifier: NCT01719627. https://www.clinicaltrials.gov/ct2/show/NCT01719627. Accessed May 30, 2019
  17. Fox J, Herrera C, Tiraboschi JM, et al. A Phase IV PrEP study reveals limited ex vivo potency of oral maraviroc against HIV-1. Abstract presented at: 22nd Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, WA. Abstract 86LB. http://www.croiconference.org/sessions/phase-iv-prep-study-reveals-limited-ex-vivo-potency-oral-maraviroc-against-hiv-1. Accessed May 30, 2019
  18. 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;70(3):242-249.
  19. Gulick RM, Wilkin TJ, Chen YQ, et al. Phase 2 safety and tolerability study of maraviroc-containing regimens to prevent HIV infection in women (HPTN 069/ACTG A5305): a randomized trial. Ann Intern Med. 2017;167(6):384-393.
  20. McGowan I, Nikiforov A, Young A, et al. PrEP impact on T-cell activation and explant infection: HPTN 069/ACTG 5305 substudy. Abstract presented at: 23rd Conference on Retroviruses and Opportunistic Infections (CROI); February 22-25, 2016; Boston, MA. Abstract 104. http://www.croiconference.org/sessions/prep-impact-t-cell-activation-and-explant-infection-hptn-069actg-5305-substudy. Accessed May 30, 2019


Last Reviewed: May 30, 2019