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FDA-approved

Investigational

Vorinostat  Audio icon

Other Names: MK-0683, suberoylanilide hydroxamic acid (SAHA), VOR, Zolinza
Drug Class: Histone Deacetylase Inhibitors
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
Company: Merck & Co., Inc.
Phase of Development: Phase II
(Compound details obtained from ChemIDplus Advanced1 and NIAID Therapeutics Database2)
Patent Version Content

Pharmacology


Mechanism of Action: Histone deacetylase inhibitor (HDACi). Vorinostat, a hydroxamic acid, is a pan-HDACi of class I and II HDACis.3 In HIV-1 latency, HDACis 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 promotes histone acetylation (hyperacetylation) of lysine residues by histone acetyltransferases (HATs), leading to chromatin relaxation and transcriptional activation.3,4 

T1/2: As an FDA-approved treatment for cutaneous T-cell lymphoma, vorinostat half-life properties have been previously described. Following oral administration of  vorinostat in patients with advanced cancer, the mean terminal half-life of vorinostat and its two inactive metabolites, O-glucuronide and 4-anilino-4-oxobutanoic acid, was approximately 2 hours, 2 hours, and 11 hours, respectively.5  

Metabolism/Elimination: Vorinostat is eliminated primarily through metabolism via glucuronidation and hydrolysis (major pathways), followed by β-oxidation. Cytochrome P450 (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. Urinary recovery of the inactive metabolites O-glucuronide and 4-anilino-4-oxobutanoic acid at steady state accounted for approximately 16% and 36%, respectively, of a vorinostat dose.5

Resistance: Resistance to vorinostat in the context of HIV infection has not been described.


Dosing in Clinical Trials


Vorinostat is administered orally.6,7

Phase II (HIV-infected adults receiving suppressive combination antiretroviral therapy (cART), with HIV-1 plasma RNA <50 copies/mL for at least 3 years and CD4 count >500 cells/µL)

  • Pilot study to determine the safety and efficacy of vorinostat in inducing HIV transcription
    Vorinostat 400 mg once daily for 14 days, in combination with cART.6,8
Phase I/II (HIV-infected adults receiving stable cART, with plasma HIV-1 RNA <50 copies/mL for at least 6 months)

  • Study to determine the efficacy of vorinostat in inducing HIV RNA expression
    Vorinostat 400 mg single dose, followed by multiple repeated short interval dosing with vorinostat 400 mg once daily (total of 8 weekly dosing cycles), in combination with cART.7,9  
A proof-of-concept study of single-dose vorinostat in combination with cART was also completed.10


Adverse Events


In a Phase II study of 20 HIV-infected adults on suppressive cART where oral vorinostat 400 mg was administered once daily for 14 days, 90% of study participants experienced a grade 1 or 2 adverse event (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.7 


Drug Interactions


As an FDA-approved treatment for cutaneous T-cell lymphoma, vorinostat drug interactions have been previously described. In this context, 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-glycoprotein (P-gp) and is not likely to inhibit P-gp at a serum concentration of 2 µM (Cmax) in humans.5 

Vorinostat drug interactions in the context of HIV infection are unknown.


References


1. United States National Library of Medicine. ChemIDplus Advanced. Last accessed on April 7, 2014.

2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Last accessed on April 7, 2014.

3. Rasmussen TA, Tolstrup M, Winckelmann A, Ostergaard L, Søgaard OS. Eliminating the latent HIV reservoir by reactivation strategies. Hum Vaccin Immunother. 2013 Apr 1;9(4):790-799. Last accessed on April 7, 2014.

4. Matalon S, Rasmussen TA, Dinarello CA. Histone Deacetylase Inhibitors for Purging HIV-1 from the Latent Reservoir. Mol Med. 2011 May-Jun;17(5-6):466-72. Last accessed on April 7, 2014.

5. Merck Sharp & Dohme Corp. Zolinza: Full Prescribing Information, April 2013. DailyMed. Last accessed on April 7, 2014. 

6. 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. Last accessed on April 7, 2014.

7. 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. Last accessed on April 7, 2014.

8. Elliott J, Solomon A, Wightman F, et al. The Safety and Effect of Multiple Doses of Vorinostat on HIV Transcription in HIV-Infected Patients Receiving Combination Antiretroviral Therapy. Abstract presented at: 20th Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2013; Atlanta, GA. Abstract 50LB. Last accessed on April 7, 2014.

9. Archin NM, Bateson R, Tripathy M, et al. HIV-1 Expression within Resting CD4 T-Cells Following Multiple Doses of Vorinostat. J Infect Dis. 2014 Mar 11. [Epub ahead of print]. Last accessed on April 7, 2014. 

10. Archin NM, Liberty AL, Kashuba AD, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012 Jul 25;487(7408):482-5. Last accessed on April 7, 2014.


Last Reviewed: April 7, 2014

Last Updated: April 25, 2014


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