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Drugs

Valproic Acid

Other Names: Depakene, Depakote, Depakote ER, Epival, VPA, divalproex sodium, valproate Drug Class: Latency-Reversing Agents
Molecular Formula: CH16 O2
Registry Number: 99-66-1 (CAS) Chemical Name: 2-propylpentanoic acid Chemical Class: Other Carboxylic Acid Derivatives Organization: AbbVie Inc.; Abbott Laboratories Phase of Development:

Valproic acid is in Phase II development as a latency-reversing agent for HIV.


Chemical Image:

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valproic acid

valproic acid

Molecular Weight: 144.2124


(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 Treatment Action Group website,3 and Depakote ER full prescribing information4)

Pharmacology


Mechanism of Action: Latency-reversing agent, specifically a histone deacetylase inhibitor (HDACi).3 Valproic acid is a carboxylate-based non-specific HDACi that does not specifically target HDAC-1 or HDAC-2. HDAC-1 and HDAC-2 are 2 of the primary HDACs that, along with HDAC-3, are thought to prevent HIV-1 expression.5 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.5,6 Some research suggests that the activity of HDACis in inducing HIV transcription may not be caused by direct effects on histone acetylation, but may be caused by effects on other nonhistone proteins.7-9

Half-life (T½): Both valproic acid and divalproex sodium dissociate to the valproate ion in the gastrointestinal tract. Following oral administration of valproate monotherapy (250–1,000 mg), the mean terminal half-life ranged from 9 hours to 16 hours.4,10

Metabolism/Elimination: Valproate is metabolized primarily in the liver. Thirty percent to 50% of an administered valproate dose is excreted in urine as a glucuronide conjugate. Typically, over 40% of the dose is eliminated by the other major metabolic pathway—mitochondrial β-oxidation—and less than 15% to 20% of a dose is eliminated by other oxidative mechanisms. Unchanged drug in the urine accounts for less than 3% of a dose.4,10


Clinical Trials



Study Identifiers: CTN-205; NCT00289952
Sponsor: McGill University Health Center
Phase: II
Study Purpose: The purpose of this study was to determine if co-administration of valproic acid with ART can reduce the size of the latent HIV reservoir.
Study Population: Participants were HIV-infected adults who were receiving a stable ART regimen for at least the past 12 months. Participants had HIV RNA <50 copies/mL for at least 12 months and CD4 counts ≥200 cells/mm3.
Dosing: Participants were randomly assigned to 1 of the following 2 groups:
  • Group 1: Oral valproic acid (Epival) 500 mg administered twice daily (adjusted to therapeutic range) together with ART for 16 weeks, followed by ART alone for 32 weeks
  • Group 2: ART alone for 16 weeks, followed by oral valproic acid (Epival) 500 mg administered twice daily (adjusted to therapeutic range) together with ART for 32 weeks11-13

*This study has been completed.

Selected Study Results:


Study Identifier:
NCT00614458
Sponsor: University of North Carolina, Chapel Hill
Phase: II
Study Purpose: The purpose of this study was to determine if adding raltegravir and valproic acid to ART can decrease the amount of latent HIV.
Study Population: Participants were HIV-infected adults who were receiving a stable ART regimen. Participants had HIV RNA <50 copies/mL for at least 6 months and CD4 counts >300 cells/mm3.
Dosing: Participants received raltegravir 400 mg and valproic acid (Depakote ER) 500–750 mg, both administered twice daily, together with ART.14,15

*This study has been completed.

Selected Study Results:


Adverse Events


In CTN-205 (NCT00289952), study withdrawals due to adverse events (AEs) were common during valproic acid treatment and increased with treatment duration.13

In the study investigating whether adding raltegravir and valproic acid to ART could reduce the size of the latent HIV reservoir (NCT00614458), no significant AEs were noted. Minor or transient AEs were reported, but these were not clearly related to valproic acid.14,15

Additional AEs known to be associated with valproic acid are described in the FDA-approved Depakene Full Prescribing Information and Depakote ER Full Prescribing Information.4,10


Drug Interactions


Coadministration of drugs that affect hepatic enzyme levels, particularly glucuronosyltransferases, may increase the clearance of valproic acid. Inhibitors of CYP450 isoenzymes are expected to have little effect on valproic acid clearance.4

In a study of 6 HIV-infected patients, valproic acid (250 or 500 mg administered every 8 hours) was shown to inhibit glucuronidation of zidovudine (100 mg administered every 8 hours) and decrease the clearance of zidovudine by 38%. The half-life of zidovudine was unaffected.4,16

The pharmacokinetic effects of valproic acid (250 mg twice daily) coadministered with efavirenz (600 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) have been studied in HIV-infected adults. Study results indicate that valproic acid coadministered with either efavirenz or lopinavir/ritonavir does not cause a decrease in plasma concentrations of efavirenz or lopinavir. Trough concentrations of valproic acid are not significantly affected by efavirenz or lopinavir.17

Additional known interactions between valproic acid and coadministered drugs are described in the FDA-approved Depakene Full Prescribing Information and Depakote ER Full Prescribing Information.4,10


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: https://chem.sis.nlm.nih.gov/chemidplus/rn/99-66-1. Last accessed on July 28, 2017.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on July 28, 2017.
  3. Treatment Action Group website. Research Toward a Cure Trials. Available at: http://www.treatmentactiongroup.org/cure/trials. Last accessed on July 28, 2017.
  4. AbbVie Inc. Depakote ER: full prescribing information, May 2017. DailyMed. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dc024ce-efc8-4690-7cb5-639c728fccac. Last accessed on July 28, 2017.
  5. 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105138/. Last accessed on July 28, 2017.
  6. Rasmussen TA, Tolstrup M, Winckelmann A, Østergaard L, Søgaard OS. Eliminating the latent HIV reservoir by reactivation strategies: Advancing to clinical trials. Hum Vaccin Immunother. 2013 Apr;9(4):790-9. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903897/. Last accessed on July 28, 2017.
  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 May 17;288(20):14400-7. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656295/. Last accessed on July 28, 2017.
  8. 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 Nov 13;10(11):e1004473. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231123/. Last accessed on July 28, 2017.
  9. Shirakawa K, Chavez L, Hakre S, Calvanese V, Verdin E. Reactivation of latent HIV by histone deacetylase inhibitors. Trends Microbiol. 2013 Jun;21(6):277-285. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685471/. Last accessed on July 28, 2017.
  10. AbbVie Inc. Depakene: full prescribing information, May 10, 2017. DailyMed. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b4331f5-4475-417a-6a9d-09c2f8334235. Last accessed on July 28, 2017.
  11. McGill University Health Center. Use of Valproic Acid to Purge HIV From Resting CD4+ Memory Cells/ A Proof-of-Concept Study. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 8, 2006. NLM Identifier: NCT00289952. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00289952. Last accessed on July 28, 2017.
  12. Routy JP, Tremblay CL, Angel JB, et al. Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV-1 reservoirs: results from a multicentre randomized clinical study. HIV Med. 2012 May;13(5):291-6. Available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1468-1293.2011.00975.x/full. Last accessed on July 28, 2017.
  13. Routy JP, Angel JB, Spaans JN, et al. Design and Implementation of a Randomized Crossover Study of Valproic Acid and Antiretroviral Therapy to Reduce the HIV Reservoir. HIV Clin Trials. 2012 Nov-Dec;13(6):301-7. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815453/. Last accessed on July 28, 2017.
  14. University of North Carolina, Chapel Hill. 10493 - MK-0518 Intensification and HDAC Inhibition in Depletion of Resting CD4+ T Cell HIV Infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 31, 2008. NLM Identifier: NCT00614458. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00614458. Last accessed on July 28, 2017.
  15. Archin NM, Cheema M, Parker D, et al. Antiretroviral Intensification and Valproic Acid Lack Sustained Effect on Residual HIV-1 Viremia or Resting CD4+ Cell Infection. PLoS One. 2010 Feb 23;5(2):e9390. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826423/. Last accessed on July 28, 2017.
  16. Lertora JJ, Rege AB, Greenspan DL, et al. Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with human immunodeficiency virus. Clin Pharmacol Ther. 1994 Sep;56(3):272-8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7924122. Last accessed on July 28, 2017.
  17. DiCenzo R, Peterson D, Cruttenden K, et al. Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults. Antimicrob Agents Chemother. 2004 Nov;48(11):4328-31. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC525398/. Last accessed on July 28, 2017.
 


Last Reviewed: July 28, 2017