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FDA-approved

Investigational

Valproic Acid  Audio icon

Other Names: Depakene, Depakote, Depakote ER, divalproex sodium, Epival, pentanoic acid, valproate, VPA
Drug Class: Histone Deacetylase Inhibitors
Molecular Formula: CH16 O2
Registry Number: 99-66-1 (CAS)
Chemical Name: 2-propylpentanoic acid
Chemical Class: Other Carboxylic Acid Derivatives
Company: AbbVie Inc.; Abbott Laboratories
Phase of Development: Phase II. In Phase II studies, valproic acid in combination with antiretroviral therapy (ART) was found to be ineffective in reducing latent HIV in CD4 T cells. 
Chemical Image:
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valproic acid
valproic acid
Molecular Weight: 144.2124

(Compound details obtained from ChemIDplus Advanced1, NIAID Therapeutics Database2, HIV Medicine article3, and PloS One article4)
Patent Version Content

Pharmacology


Mechanism of Action: Histone deacetylase (HDAC) inhibitor. Valproic acid is a carboxylate-based non-specific HDAC inhibitor that does not specifically target HDAC-1 or HDAC-2, the primary HDAC inhibitors thought to prevent HIV-1 expression.5 In HIV-1 latency, HDAC inhibitors 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.5,6

Note: In Phase II studies, valproic acid added to combination antiretroviral therapy (cART) was found to be ineffective in reducing the latent HIV reservoir.3,4

: As an FDA-approved treatment for acute manic or mixed episodes of bipolar disorder, some types of seizures, and migraine headache prophylaxis, valproate properties have been previously described. (Both valproic acid and divalproex sodium dissociate to the valproate ion in the gastrointestinal tract.) Following oral administration of valproate monotherapy (250 to 1000 mg), the mean terminal half-life ranged from 9 hours to 16 hours.7,8 

Metabolism/Elimination: Valproate is metabolized primarily in the liver. In adult patients on valproate monotherapy, 30% to 50% of an administered dose appears 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. Less than 3% of a dose is excreted as unchanged drug in the urine.7,8 

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


Dosing in Clinical Trials


Phase II (HIV-infected adults receiving cART, with viral load less than 50 copies/mL for at least 1 year)

  • CTN-205: Study to determine if co-administration of valproic acid with cART can reduce the size of latent HIV reservoirs in CD4 T cells.
Two experimental groups

Group 1: Oral valproic acid 500 mg administered twice daily (adjusted to therapeutic range) together with cART for 16 weeks, followed by cART alone for 32 weeks.

Group 2: cART alone for 16 weeks, followed by oral valproic acid 500 mg administered twice daily (adjusted to therapeutic range) together with cART for 32 weeks.3,9


Phase II
(HIV-infected adults receiving cART with viral load less than 50 copies/mL for at least 6 months)

  • Study to determine if adding raltegravir and valproic acid to cART can reduce the size of latent HIV reservoirs in CD4 T cells.

Raltegravir 400 mg and valproic acid 500 mg to 750 mg, both administered twice daily together with cART.4,10


Adverse Events


In CTN-205, study withdrawals due to adverse events (AEs) were common during valproic acid treatment and increased with treatment duration.11

In the study investigating whether adding raltegravir and valproic acid to cART could reduce the size of HIV latent reservoirs in CD4 T cells, no significant AEs were noted. Minor AEs were reported, but these were not clearly related to valproic acid.4


Drug Interactions


As an FDA-approved treatment for acute manic or mixed episodes of bipolar disorder, some types of seizures, and migraine headache prophylaxis, valproic acid drug interactions have been previously described. Co-administration of drugs that affect hepatic enzyme levels, particularly glucuronosyltransferases, may increase the clearance of valproic acid. Inhibitors of cytochrome P450 isoenzymes are expected to have little effect on valproic acid clearance.7

In a study of six 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.7,12

The pharmacokinetic effects of valproic acid (250 mg twice daily) co-administered 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 co-administration of valproic acid with either efavirenz or lopinavir/ritonavir decreases plasma concentrations of efavirenz or lopinavir. Trough concentrations of valproic acid are not significantly affected by efavirenz or lopinavir.13


References


1. United States National Library of Medicine. ChemIDplus Advanced. Last accessed on April 30, 2014.

2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Last accessed on April 30, 2014.

3. 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. Last accessed on April 30, 2014.

4. 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. Last accessed on April 30, 2014.

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. Last accessed on April 30, 2014.

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. Last accessed on April 30, 2014.

7. AbbVie Inc. Depakote ER: Full Prescribing Information, 2014. DailyMed. Last accessed on April 30, 2014.

8. AbbVie Inc. Depakene: Full Prescribing Information, 2014. DailyMed. Last accessed on April 30, 2014.

9. 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. Last accessed on April 30, 2014.

10. 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. Last accessed on April 30, 2014.

11. 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. Last accessed on April 30, 2014.

12. 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. Last accessed on April 30, 2014.

13. 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. Last accessed on April 30, 2014.


Last Reviewed: April 30, 2014

Last Updated: April 30, 2014


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