Drugs

Vorinostat

Other Names: MK-0683, VOR, Zolinza, suberoylanilide hydroxamic acid (SAHA) Drug Class: Latency-Reversing Agents
Molecular Formula: C14 H20 N2 O3
Registry Number: 149647-78-9 (CAS) Chemical Name: 8-(hydroxyamino)-8-oxo-N-phenyl-octanamide Chemical Class: Other Carboxylic Acid Derivatives Organization: Merck & Co., Inc. Phase of Development: Vorinostat is in Phase 2 development as a latency-reversing agent for HIV.

Chemical Image:

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vorinostat

vorinostat

Molecular Weight: 264.323

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and Treatment Action Group website3)

Pharmacology


Mechanism of Action: Latency-reversing agent, specifically a histone deacetylase inhibitor (HDACi).3 Vorinostat, a hydroxamic acid, is a pan-HDACi of class I and II histone deacetylases (HDACs).4 In HIV-1 latency, HDACs are recruited to the proviral 5' long terminal repeat (LTR), where they catalyze deacetylation of lysine residues on histones, resulting in chromatin condensation on nucleosome 1 (nuc-1) and preventing HIV transcription. Inhibition of HDAC activity, however, causes histone acetylation (hyperacetylation) of lysine residues by histone acetyltransferases (HATs). This leads to chromatin relaxation and transcriptional activation of HIV.4,5 Some research suggests that the activity of HDACs in inducing HIV transcription may not be caused by direct effects on histone acetylation, but may be caused by effects on other nonhistone proteins.6-8

Half-life (T½): After oral administration of vorinostat in patients with advanced cancer, the mean terminal half-life of vorinostat was approximately 2 hours, and the mean terminal half-lives of vorinostat’s two inactive metabolites, O-glucuronide and 4-anilino-4-oxobutanoic acid, were approximately 2 hours and 11 hours, respectively.9

Metabolism/Elimination: Vorinostat is eliminated primarily through metabolism via glucuronidation and hydrolysis (major pathways), followed by β-oxidation. CYP enzymes have a negligible role in vorinostat metabolism. Less than 1% of a total vorinostat dose is recovered as unchanged drug in urine, indicating that vorinostat is not excreted renally. At steady state, approximately 16% of a vorinostat dose is excreted in the urine as the inactive metabolite O-glucuronide and approximately 36% is excreted in the urine as the inactive metabolite 4-anilino-4-oxobutanoic acid.9


Select Clinical Trials


Study Identifier: NCT01319383
Sponsor: University of North Carolina, Chapel Hill
Phase: 1/2
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to determine the efficacy of vorinostat in inducing HIV RNA expression within resting CD4 cells after single and multiple short-interval vorinostat doses.
Study Population: Participants were adults with HIV who were receiving stable ART and who had HIV-1 RNA <50 copies/mL and CD4 cell counts >300 cells/mm3 for at least 6 months before study entry.10,11
Selected Study Results:

Study Identifiers: (1) SEARCH 019; NCT02475915 and (2) SEARCH 026; NCT02470351
Sponsor: South East Asia Research Collaboration with Hawaii
Phase: 1/2
Status: These studies have been completed.
Study Purpose:

  • The purpose of the open-label SEARCH 019 trial was to compare the safety and effectiveness of vorinostat plus hydroxychloroquine plus maraviroc (VHM) in combination with ART versus ART alone in controlling HIV RNA during an analytical treatment interruption (ATI) that followed.
  • SEARCH 026 was a substudy designed to evaluate central nervous system (CNS) effects in SEARCH 019 participants.
Study Population: Participants were adults with HIV who initiated ART during acute HIV infection. Participants had HIV RNA <50 copies/mL for more than 48 weeks and CD4 counts ≥450 cells/mm3.12-14

Selected Study Results:

Study Identifier: NCT01365065
Sponsor: Bayside Health
Phase: 2
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to determine the ability of vorinostat to induce HIV RNA expression within resting CD4 cells after 14 days of daily vorinostat.
Study Population: Participants were adults with HIV who were receiving suppressive ART. Participants had HIV-1 RNA <50 copies/mL for at least 3 years and CD4 counts >500 cells/mm3.3,15
Selected Study Results:

Study Identifiers: RIVER trial; NCT02336074 
Sponsor: Imperial College London
Phase: 2
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label, proof-of-concept study is to determine whether a combined approach using ART plus two anti-HIV vaccines and vorinostat can lead to greater reductions in the size of the latent HIV reservoir when compared to ART alone.
Study Population: Participants are adults with HIV. Participants who are enrolled in this study have been diagnosed with primary HIV infection within 4 weeks of enrollment.16,17

Selected Study Results:

Other HIV-related trials involving vorinostat include:

  • XTRA trial (NCT03212989): A Phase 1 study that will evaluate the effects of vorinostat and HIV-1 antigen expanded specific T-cell therapy on persistent HIV-1 infection in individuals with HIV on suppressive ART. This study is currently recruiting participants.18
  • ACTG A5366 (NCT03382834): An early Phase 1 study that is investigating whether the selective estrogen receptor modulator tamoxifen can enhance vorinostat’s ability to reverse HIV latency in post-menopausal women with HIV who are virologically suppressed on ART. This study is ongoing, but not recruiting participants.19
  • VOR-07 study (NCT03803605): A Phase 1 study that will evaluate the effects of vorinostat and the investigational broadly neutralizing antibody VRC07-523LS on persistent HIV-1 infection in individuals with HIV on suppressive ART. This study is currently recruiting participants.20


Adverse Events


NCT01319383:

In this Phase 1/2 study, no vorinostat-associated adverse events (AEs) were reported during single limited exposures to vorinostat in eight participants with HIV on suppressive ART. No AEs greater than Grade 1 severity occurred.21 During multiple short-interval vorinostat dosing (every 24 hours) in five participants, some mild, transient gastrointestinal symptoms and headache occurred (all below Grade 1 severity). Transient thrombocytopenia occurred in all participants. Only one participant developed Grade 1 thrombocytopenia, and this toxicity level was observed at just a single study visit.22 A neurocognitive assessment performed on all five participants at baseline and study end found no significant change in neurocognitive functioning.23

During another study conducted under this same protocol evaluating single dosing, paired dosing, and multiple dosing (every 72 hours) of vorinostat, similar AEs were reported. Mild and transient gastrointestinal symptoms (below Grade 1) occurred and transient thrombocytopenia (below Grade 1) was seen in the participants who received multiple vorinostat dosing.11

SEARCH 019 (NCT02475915) and SEARCH 026 (NCT02470351):

In the SEARCH 019 study, serious adverse events (SAEs) occurred in two out of 10 participants in the VHM arm. One of the two participants discontinued the study because of renal insufficiency plus low platelets (VHM-related), and the other participant had diarrhea (possibly due to food poisoning/VHM). In terms of nonserious AEs, 81 events occurred in 10 ART plus VHM participants, and 37 events occurred in five ART-only participants. Significantly more participants in the ART plus VHM group than in the ART-only group experienced nonserious thrombocytopenia and elevated creatinine levels. There were no reports of acute retroviral syndrome following ATI. Additionally, following ATI, there were no new resistance mutations detected and no reports of virological failure after participants resumed ART.12,24

The CNS substudy found that VHM treatment did not result in detectable CSF HIV RNA or in lasting adverse effects—this was based on CSF inflammatory measures, neuropsychological testing, and magnetic resonance spectroscopy (MRS). ATI was found to be associated with CNS immune activation and detectable HIV RNA in CSF.14,25

NCT01365065:

In this Phase 2 study, 90% (18/20) of study participants experienced a Grade 1 or 2 AE, with nausea, diarrhea, fatigue, and thrombocytopenia being the most common AEs. There was no occurrence of AEs of a higher grade, dose modifications, or drug discontinuations. Significant and prolonged changes in host gene expression were observed at Day 84.6,26 Extended follow up for 24 months demonstrated that vorinostat did not cause any long-term safety issues or changes in HIV expression.27

RIVER trial (NCT02336074):

In this Phase 2 study, 97% (29/30) of participants in the intervention arm (ART plus two therapeutic HIV vaccines plus vorinostat) experienced an AE. Seventy percent of these AEs were mild and 23% were moderate in intensity. In comparison, in the ART-only arm, 73% (22/30) of participants experienced an AE, 33% of which were mild and 20% of which were moderate. No intervention-related SAEs were reported.16,17,28

Additional AEs known to be associated with vorinostat use are described in the FDA-approved Full Prescribing Information for Zolinza.9


Drug Interactions


Previous studies have indicated that vorinostat at the 400-mg dose level does not inhibit CYP-drug-metabolizing enzymes. Because vorinostat is not eliminated via CYP pathways, drug-drug interactions between vorinostat and agents that are known CYP inhibitors or inducers are not anticipated. Vorinostat is not a substrate of human P-gp and is not likely to inhibit P-gp at a serum concentration of 2 µM (Cmax) in humans.9

An in vitro study investigating the interaction of CYP modulators (nevirapine, cobicistat, rifampin, and ketoconazole) on vorinostat in human hepatocytes found that vorinostat metabolism was affected by CYP modulators; however, there was no meaningful change in the clearance of vorinostat.29

During the Phase 2 study (NCT01365065) which involved 20 participants who received at least three ARV agents and once-daily vorinostat over 14 days, there were no significant interactions between vorinostat and ART.6

Additional known interactions between vorinostat and coadministered drugs are described in the FDA-approved Full Prescribing Information for Zolinza.


References


  1. United States National Library of Medicine. ChemIDplus Advanced: Vorinostat. https://chem.nlm.nih.gov/chemidplus/rn/149647-78-9. Accessed June 5, 2019
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed June 5, 2019
  3. Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed June 5, 2019
  4. Rasmussen TA, Tolstrup M, Winckelmann A, Østergaard L, Søgaard OS. Eliminating the latent HIV reservoir by reactivation strategies. Hum Vaccines Immunother. 2013;9(4):790–799.
  5. Matalon S, Rasmussen TA, Dinarello CA. Histone deacetylase inhibitors for purging HIV-1 from the latent reservoir. Mol Med. 2011;17(5-6):466-472.
  6. Elliott JH, Wightman F, Solomon A, et al. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog. 2014;10(11). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231123/. Accessed June 5, 2019
  7. Bartholomeeusen K, Fujinaga K, Xiang Y, Peterlin BM. Histone deacetylase inhibitors (HDACis) that release the positive transcription elongation factor b (P-TEFb) from its inhibitory complex also activate HIV transcription. J Biol Chem. 2013;288(20):14400-14407. doi:10.1074/jbc.M113.464834
  8. Shirakawa K, Chavez L, Hakre S, Calvanese V, Verdin E. Reactivation of latent HIV by histone deacetylase inhibitors. Trends Microbiol. 2013;21(6):277-285. doi:10.1016/j.tim.2013.02.005
  9. Merck Sharp & Dohme Corp. Zolinza: full prescribing information, December 2018. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092. Accessed June 5, 2019
  10. University of North Carolina, Chapel Hill. A Phase I/II investigation of the effect of vorinostat (VOR) on HIV RNA expression in the resting CD4+ T cells of HIV-infected patients receiving stable antiretroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 17, 2011. NLM Identifier: NCT01319383. https://www.clinicaltrials.gov/ct2/show/NCT01319383. Accessed June 5, 2019
  11. Archin NM, Kirchherr JL, Sung JAM, et al. Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency. J Clin Invest. 127(8):3126-3135. doi:10.1172/JCI92684
  12. South East Asia Research Collaboration with Hawaii. A randomized study to compare the efficacy of vorinostat/hydroxychloroquine/maraviroc (VHM) in controlling HIV after treatment interruption in subjects who initiated ART during acute HIV infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 3, 2015. NLM Identifier: NCT02475915. https://clinicaltrials.gov/ct2/show/study/NCT02475915. Accessed June 5, 2019
  13. Kroon E, Ananworanich J, Eubanks K, et al. Effect of vorinostat, hydroxychloroquine and maraviroc combination therapy on viremia following treatment interruption in individuals initiating ART during acute HIV infection. Abstract presented at: 21st International AIDS Conference (AIDS 2016); July 18-22, 2016; Durban, South Africa. Abstract TUAX0101LB. http://programme.aids2016.org/Abstract/Abstract/10535. Accessed June 5, 2019
  14. South East Asia Research Collaboration with Hawaii. Study SEARCH 026Assessment of the HIV CNS reservoir, neurological and neuro-cognitive effects, and source of rebound HIV in CNS in subjects participating in Study SEARCH 019. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 2, 2015. NLM Identifier: NCT02470351. https://clinicaltrials.gov/ct2/show/NCT02470351. Accessed June 5, 2019
  15. Bayside Health. A pilot study to assess the safety and effect on HIV transcription of vorinostat in patients receiving suppressive combination anti-retroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 1, 2011. NLM Identifier: NCT01365065. https://www.clinicaltrials.gov/ct2/show/NCT01365065. Accessed June 5, 2019
  16. Imperial College London. Research in viral eradication of HIV reservoirs. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 23, 2014. NLM Identifier: NCT02336074. https://www.clinicaltrials.gov/ct2/show/NCT02336074. Accessed June 5, 2019
  17. Fidler S. RIVER research in viral eradication of HIV reservoirs: a two-arm (proof of concept) randomised Phase II trial vorinostat plus a prime boost vaccine. Slides presented at: International AIDS Conference (AIDS 2018): July 23-27, 2018; Amsterdam, the Netherlands. https://programme.aids2018.org/PAGMaterial/PPT/6106_3214/RIVER%20presentation%20at%20IAS%2024.7.2018%20final%20draft.pptx. Accessed June 5, 2019
  18. University of North Carolina, Chapel Hill. IGHID 11627 - A Phase I study to evaluate the effects of vorinostat and HIV-1 antigen expanded specific T cell therapy (HXTC) on persistent HIV-1 infection in HIV-infected individuals started on antiretroviral therapy (The XTRA Study). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 11, 2018. NLM Identifier: NCT03212989. https://clinicaltrials.gov/ct2/show/study/NCT03212989. Accessed June 5, 2019
  19. National Institute of Allergy and Infectious Diseases (NIAID). Selective estrogen receptor modulators to enhance the efficacy of viral reactivation with histone deacetylase inhibitors. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 19, 2017. NLM Identifier: NCT03382834. https://clinicaltrials.gov/ct2/show/record/NCT03382834. Accessed June 5, 2019
  20. University of North Carolina, Chapel Hill. IGHID 11802 - Combination Therapy With the Novel Clearance Modality (VRC07-523LS) and the Latency Reversal Agent (Vorinostat) to Reduce the Frequency of Latent, Resting CD4+ T Cell Infection (The VOR-07 Study). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on: January 10, 2019. NLM Identifier: NCT03803605. https://clinicaltrials.gov/ct2/show/NCT03803605. Accessed June 5, 2019
  21. Archin NM, Liberty AL, Kashuba AD, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012;487(7408):482-485. doi:10.1038/nature11286
  22. Archin NM, Bateson R, Tripathy M, et al. HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat. J Infect Dis. 2014;210(5):728-735. doi:10.1093/infdis/jiu155
  23. Robertson K, Kuruc J, Gay C, Archin N, Eron J, Margolis D. Preliminary assessment of the neurocognitive effects of vorinostat administration in HIV eradication. Abstract presented at: International AIDS Conference; July 20-25, 2014; Melbourne, Australia. Abstract WEPE018. http://www.abstract-archive.org/Abstract/Share/18721. Accessed June 5, 2019
  24. Kroon E, Ananworanich J, Eubanks K, et al. Effect of vorinostat, hydroxychloroquine and maraviroc combination therapy on viremia following treatment interruption in individuals treated during acute HIV infection. 21st International AIDS Conference (AIDS 2016); July 18-22, 2016; Durban, South Africa. Mascolini: Vorinostat, HCQ, Maraviroc Do Not Delay Time to Rebound After Interruption. Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2016. http://www.natap.org/2016/IAC/IAC_07.htm. Accessed June 5, 2019
  25. Kroon E, Ananworanich J, Le LT, et al. Central nervous system impact of vorinostat, hydroxychloroquine and maraviroc combination therapy followed by treatment interruption in individuals treated during acute HIV infection (SEARCH 026). Poster presented at: International AIDS Conference (AIDS 2016); July 18-22, 2016; Durban, South Africa. Poster LBPE005. http://programme.aids2016.org/PAGMaterial/eposters/0_10588.pdf. Accessed June 5, 2019
  26. Elliott J, Solomon A, Wightman F, et al. The safety and effect of multiple doses of vorinostat in HIV-infected patients receiving combination antiretroviral therapy. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2013; Atlanta, GA. Abstract 50LB. https://web.archive.org/web/20190328194445/http://napwha.org.au/sites/default/files/CROI%202013%20vorinostat%20final%202.pdf. Accessed June 5, 2019
  27. Mota TM, Rasmussen TA, Rhodes A, et al. No adverse safety or virological changes 2 years following vorinostat in HIV-infected individuals on antiretroviral therapy. AIDS. 2017;31(8):1137-1141. doi:10.1097/QAD.0000000000001442
  28. Fidler S, Stohr W, Pace M, et al. A randomised controlled trial comparing the impact of antiretroviral therapy (ART) with a “Kick-and-Kill” approach to ART alone on HIV reservoirs in individuals with primary HIV infection (PHI); RIVER trial. Abstract presented at: International AIDS Conference (AIDS 2018); July 23-27, 2018; Amsterdam, the Netherlands. Abstract TUAA0202LB. http://programme.aids2018.org/Abstract/Abstract/12977. Accessed June 5, 2019
  29. Shaik H, Pillai VC, Parise RA, et al. Metabolism of vorinostat in primary human hepatocytes is not affected by HAART drugs, nevirapine and cobicistat. Poster presented at: 2014 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition; November 2-6, 2014; San Diego, CA. Poster T2293. Available at: http://abstracts.aaps.org/Verify/AAPS2014/PosterSubmissions/T2293.pdf. Accessed July 12, 2017


Last Reviewed: June 5, 2019