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Disulfiram

Other Names: Antabuse, DSF, tetraethylthiuram disulfide Drug Class: Latency-Reversing Agents
Molecular Formula: C10 H20 N2 S4
Registry Number: 97-77-8 (CAS) Chemical Name: Disulfide, bis(diethylthiocarbamoyl) Chemical Class: Thiuram disulfides Phase of Development: Disulfiram is in Phase I/II development as a latency-reversing agent for HIV.

Chemical Image:

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disulfiram

disulfiram

Molecular Weight: 296.546

(Compound details obtained from ChemIDplus Advanced,1 Treatment Action Group website,2 ChemMedChem article,3 and ClinicalTrials.gov4)

Pharmacology


Mechanism of Action: Latency-reversing agent, specifically a phosphatase and tensin homolog (PTEN) inhibitor.2,5 Disulfiram is an FDA-approved drug used for aiding in the management of alcoholism. As such, it works by disrupting the metabolism of alcohol through inhibition of aldehyde dehydrogenase (ALDH).6,7 Disulfiram also inhibits dopamine β-hydroxylase and has been studied as a treatment for cocaine dependence.8,9 It is also proposed to induce proteasome inhibition and apoptosis of cancer cells and has been studied as an anticancer therapy.9

As an investigational agent for reactivating latent HIV expression, the potential mechanism by which disulfiram is thought to function is through reduction of PTEN expression, which results in activation of the PI3K/Akt signaling pathway.10,11 Data analyzed from a disulfiram dose-escalation study in individuals with HIV suggest that the disulfiram metabolites diethyldithiocarbamate-methyl ester (DDTC-Me) and carbamathione drive the reactivation of latent HIV.12

Half-life (T½): In a study of male alcoholics receiving 250 mg disulfiram as a single dose and as repeated doses over 12 days, the apparent half-life was 7.3 hours for disulfiram, 15.5 hours for diethyldithiocarbamate (DDTC), 22.1 hours for diethyldithiocarbamate-methyl ester (DDTC-Me), 13.9 hours for diethylamine (DEA), and 8.9 hours for carbon disulfide (CS2). CS2 in breath had an elimination half-life of 13.3 hours.13

Metabolism/Elimination: Disulfiram is a prodrug and forms multiple metabolites in vivo, including but not limited to (1) the primary metabolite DDTC, (2) the metabolite S-methyl N, N-diethylthiolcarbamate sulfoxide (DETC-MeSO), which is responsible for the disulfiram anti-alcohol effect, and (3) DDTC-Me and carbamathione, which are thought to drive reactivation of latent HIV.12,14,15 Metabolism of disulfiram occurs predominantly in the liver, and the formation of DETC-MeSO occurs mostly via CYP3A4/5, with contributions by CYP1A2, CYP2A6, CYP2E1, and CYP2D6.7,14,16 FMOs also play a role in disulfiram metabolism in the liver (FMO3) and kidney (FMO1).17

As much as 20% of a disulfiram dose may remain in the body for a week or more. Disulfiram is excreted primarily in the urine, as metabolites, and some metabolites are exhaled as CS2. Approximately 5% to 20% of a dose is excreted as unchanged drug in the feces.7


Select Clinical Trials


Study Identifier: NCT01286259
Sponsor: University of California, San Francisco
Phase: Not available
Status: This study has been completed.
Study Purpose: The purpose of this pilot study was to determine the safety of disulfiram and whether the addition of disulfiram to ART could reactivate latent HIV and reduce the size of the latent reservoir.
Study Population:

  • Participants were adults with HIV who were virologically suppressed on ART and who were receiving ART for at least 18 months. Participants had been on a stable ART regimen for at least 3 months before study entry.
  • Participants had HIV RNA <50 copies/mL for the past 12 months and CD4 counts >200 cells/mm3 for 24 weeks prior to enrollment.

Dosing: Disulfiram 500 mg was administered once daily and orally for 14 days, in combination with ART.18,19
Selected Study Results:


Study Identifier: NCT01944371
Sponsor: University of California, San Francisco
Phase: I/II
Status: This study has been completed.
Study Purpose: The purpose of this dose-escalation study was to evaluate the safety and effects of disulfiram on reactivating latent HIV.
Study Population:

  • Participants were adults with HIV who were virologically suppressed on ART (efavirenz- or ritonavir-based regimen).
  • Participants had HIV RNA <50 copies/mL for at least 3 years and CD4 counts >350 cells/mm3 during the 6 months prior to screening.

Dosing: Participants were sequentially enrolled into 1 of 3 dosing groups (500 mg, 1000 mg, and 2000 mg) and received disulfiram once daily for 3 days, in combination with ART.4,12,20,21 
Selected Study Results:


Other HIV-related studies involving disulfiram have also been conducted, including:

  • NCT01571466, a completed Phase I HIV eradication study that evaluated therapeutic vaccination with a modified vaccinia Ankara-based HIV-1 vaccine (MVA-B) administered alone and in combination with disulfiram.22,23
  • NCT03198559, a Phase I/II study that evaluated the effectiveness of a combination of 2 latency-reversing agents—high-dose disulfiram and vorinostat—in reactivating latent HIV. This study is not yet open for participant recruitment.24


Adverse Events


NCT01286259:
In this pilot study of disulfiram 500 mg administered over 14 days, no particular safety concerns associated with disulfiram were reported in 16 enrolled participants. Adverse events (AEs) that occurred during the study were of Grades I and II toxicity. One participant withdrew from the study after completing 12 days of disulfiram therapy.18,19

NCT01944371:
In this Phase I/II dose escalation study of disulfiram 500 mg to 2000 mg administered at each dose level for 3 days, no deaths, drug discontinuations, or Grade 3 or 4 AEs were reported among 30 total participants. The majority of AEs that were possibly, probably, or definitely associated with disulfiram were of Grade 1 severity and occurred in the 1000-mg or 2000-mg dose groups. These included dry mouth/dysgeusia, headache, nausea, drowsiness/lethargy, and light headedness. Seven cases of Grade 2 hypophosphatemia were reported, with 3 cases occurring in the 500-mg dose group and 2 cases each in the 1000-mg and 2000-mg dose groups.20,21

Additional AEs known to be associated with disulfiram are described in the FDA-approved Full Prescribing Information for Antabuse.6


Drug Interactions


Disulfiram is metabolized in the liver via CYP enzymes. It is a selective inhibitor of CYP2E1 activity and has been reported to have some inhibitory activity toward CYP1A2.7,14-16,25

In a drug-interaction study between disulfiram (62.5 mg daily and 250 mg daily) and standard therapeutic doses of the ARV medications efavirenz, ritonavir, and atazanavir, disulfiram was found to have no effect on the pharmacokinetics of any of the ARVs. However, efavirenz and atazanavir had significant effects on disulfiram metabolism. Efavirenz coadministered with disulfiram resulted in decreased concentrations of the disulfiram metabolite S-Methyl-N-N-diethylthiocarbamate and in increased disulfiram-mediated ALDH inhibition relative to disulfiram administered alone. When atazanavir was coadministered with disulfiram, disulfiram-mediated ALDH inhibition was reduced; therefore, disulfiram may not be effective in treating alcoholism when administered concomitantly with atazanavir.16

Additional known interactions between disulfiram and co-administered drugs are described in the FDA-approved Full Prescribing Information for Antabuse.6


References


  1. United States National Library of Medicine. ChemIDplus Advanced: Disulfiram. https://chem.nlm.nih.gov/chemidplus/rn/97-77-8. Accessed July 27, 2018.
  2. Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed July 27, 2018.
  3. Kulkarni RA, Stanford SM, Vellore NA, et al. Thiuram disulfides as pseudo-irreversible inhibitors of the lymphoid tyrosine phosphatase. ChemMedChem. 2013;8(9). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863632/. Accessed July 27, 2018.
  4. University of California, San Francisco. Short-term disulfiram administration to reverse latent HIV infection: a dose escalation study. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 12, 2013. NLM Identifier: NCT01944371. https://clinicaltrials.gov/ct2/show/NCT01944371. Accessed July 27, 2018.
  5. Archin NM, Sung JM, Garrido C, Soriano-Sarabia N, Margolis DM. Eradicating HIV-1 infection: seeking to clear a persistent pathogen. Nat Rev Microbiol. 2014;12(11):750-764.
  6. Teva Women’s Health, Inc. Antabuse: full prescribing information, May 2017. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f0ca0e1f-9641-48d5-9367-e5d1069e8680. Accessed July 27, 2018.
  7. United States National Library of Medicine. PubChem. Disulfiram. https://pubchem.ncbi.nlm.nih.gov/compound/3117.  Accessed July 27, 2018.
  8. Schroeder JP, Cooper DA, Schank JR, et al. Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine β-hydroxylase. Neuropsychopharmacology. 2010;35(12):2440-2449.
  9. Koppaka V, Thompson DC, Chen Y, et al., Thompson DC, Chen Y, et al. Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. Pharmacol Rev. 2012;64(3):520-539.
  10. Doyon G, Zerbato J, Mellors JW, Sluis-Cremer N. Disulfiram reactivates latent HIV-1 expression through depletion of the phosphatase and tensin homolog. AIDS. 2013;27(2):F7-F11.
  11. Doyon G, Zerbato J, Mellors J, Sluis-Cremer N. Mechanism by which disulfiram reactivates latent HIV-1 expression. Abstract presented at: 19th International AIDS Conference; July 22-27, 2012; Washington, DC. Abstract THPE010. http://www.abstract-archive.org/Abstract/Share/13377. Accessed July 27, 2018.
  12. Lee SA, Elliott JH, McMahon J, et al. Disulfiram reactivates latent HIV infection in a dose-dependent manner. Abstract presented at: 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy; May 26-28, 2015; Washington, DC. Abstract 11. http://regist2.virology-education.com/abstractbook/2015_4.pdf. Accessed July 27, 2018.
  13. Faiman MD, Jensen JC, Lacoursiere RB. MD. Elimination kinetics of disulfiram in alcoholics after single and repeated doses. Clin Pharmacol Ther. 1984;36(4):520-526.
  14. Faiman MD, Kaul S, Latif SA, Williams TD, Lunte CE. S-(N, N-diethylcarbamoyl)glutathione (carbamathione), a disulfiram metabolite and its effect on nucleus accumbens and prefrontal cortex dopamine, GABA, and glutamate: A microdialysis study. Neuropharmacology. 2013;75:95-105.
  15. Kharasch ED, Hankins DC, Jubert C, Thummel KE, Taraday JK. Lack of single-dose disulfiram effects on cytochrome P-450 2C9, 2C19, 2D6, and 3A4 activities: evidence for specificity toward P-450 2E1. Drug Metab Dispos. 1999;27(6):717-723.
  16. McCance-Katz EF, Gruber VA, Beatty G, et al. Interaction of disulfiram with antiretroviral medications: efavirenz increases while atazanavir decreases disulfiram effect on enzymes of alcohol metabolism. Am J Addict. 2014;23(2):137-144.
  17. Pike MG, Mays DC, Macomber DW, Lipsky JJ. Metabolism of a disulfiram metabolite, S-methylN,N-diethyldithiocarbamate, by flavin monooxygenase in human renal microsomes. Drug Metab Dispos. 2001;29(2):127-132.
  18. University of California, San Francisco. Short-term disulfiram administration to accelerate the decay of the HIV reservoir in antiretroviral-treated HIV infected individuals. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 27, 2011. NLM Identifier: NCT01286259. https://clinicaltrials.gov/ct2/show/NCT01286259. Accessed July 27, 2018.
  19. Spivak AM, Andrade A, Eisele E, et al. A pilot study assessing the safety and latency-reversing activity of disulfiram in HIV-1–infected adults on antiretroviral therapy. Clin Infect Dis. 2014;58(6):883-890.
  20. Elliott JH, McMahon JH, Chang CC, et al. Short-term disulfiram to reverse latent HIV infection: a Phase 2 dose escalation study. Lancet HIV. 2015;2(12):e520-e529.
  21. Elliott JH, McMahon JH, Hartogensis, et al. Short-term disulfiram to reverse latent HIV infection: a dose escalation study. Poster presented at: 22nd Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, WA. Poster 428LB. http://www.croiconference.org/sites/default/files/posters-2015/428LB.pdf.
  22. Hospital Clinic of Barcelona. A double-blind Phase I study to evaluate the safety of the HIV-1 vaccine MVA-B in chronic HIV-1 infected patients successfully treated with HAART. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 9, 2011. NLM Identifier: NCT01571466. https://clinicaltrials.gov/show/NCT01571466. Acessed July 27, 2018
  23. Mothe B, Climent N, Plana M, et al. Safety and immunogenicity of a modified vaccinia Ankara-based HIV-1 vaccine (MVA-B) in HIV-1-infected patients alone or in combination with a drug to reactivate latent HIV-1. J Antimicrob Chemother. 2015;70(6):1833-1842.
  24. The Peter Doherty Institute for Infection and Immunity. Combination latency reversal with high dose disulfiram plus vorinostat in HIV-infected individuals on ART (DIVA): a single arm clinical trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 14, 2017. NLM Identifier: NCT03198559. https://clinicaltrials.gov/ct2/show/NCT03198559. Accessed July 27, 2018.
  25. Frye RF, Branch RA. Effect of chronic disulfiram administration on the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and N-acetyltransferase in healthy human subjects. Br J Clin Pharmacol. 2002;53(2):155-162.


Last Reviewed: July 27, 2018