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Antabuse (Disulfiram) Has Linear Exposure-Response
Profile in Activating Latent HIV
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16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 26-28, 2015, Washington, DC
Mark Mascolini
Disulfiram (Antabuse) has a linear exposure-response profile in activating latent HIV as measured by cell-associated unspliced RNA (CA-US RNA) [1]. University of California, San Francisco (UCSF) researchers speculated that higher but still safe doses "may achieve even greater responses in CA-US RNA in future studies." Ten percent of study participants had reactivation responses larger than disulfiram exposure alone would explain.
HIV cure strategies often rely on agents that attempt to activate latent HIV in resting memory CD4 cells. Histone deacetylase inhibitors, the most-studied latency reactivators, have a modest reactivation impact, studies so far suggest. Stronger reactivators carry a higher risk of toxicity. Disulfiram, licensed to treat alcohol dependence [2], also has reactivating properties.
For alcohol dependence, disulfiram dosing starts at 500 mg daily for 1 to 2 weeks, followed by a maintenance dose of 125 to 500 mg daily. But doses up to 6 g have been used, the UCSF group noted. Disulfiram may have mild sedative effects and can cause peripheral neuropathy [2]. Because disulfiram decreases metabolism of phenytoin, it can raise phenytoin levels and cause phenytoin intoxication. But the drug has a reasonable overall safety profile. Disulfiram does not affect antiretroviral concentrations, but antiretrovirals can affect the impact of disulfiram on alcohol metabolism.
UCSF researchers and collaborators at other centers conducted a phase 1 study of disulfiram pharmacokinetics and pharmacodynamics in 30 antiretroviral-treated people with an undetectable viral load. All study participants had taken antiretrovirals for more than 3 years, had a viral load below 50 copies, and had a CD4 count above 350.
Ten people got 500 mg of disulfiram daily for 3 days, 10 people got 1000 mg for 3 days, and 10 got 2000 mg for 3 days. The investigators measured levels of disulfiram and its four metabolites (designated M1 to M4) before dosing; at hours 2 and 6 of day 1, day 2, and day 3; and on days 4 and 8. To gauge disulfiram activity, they measured changes in CA-US RNA and plasma HIV RNA. In the viral replication cycle, unspliced RNA is a late transcription product that gets packaged into viral particles budding from infected cells to serve as the primary genome of new virions.
Estimated disulfiram clearance measured 0.35 L/h (coefficient of variation 20%), while volume of distribution stood at 1.6 L and absorption constant at 0.12 h(-1). Disulfiram area under the concentration-time curve rose from 573 mg*h/L with 500 mg daily, to 2845 mg*h/L with 1000 mg, and to 8355 mg*h/L with 2000 mg. The escalating disulfiram exposure with each higher dose was greater than dose-proportional, a finding the researchers attributed to dose-dependent increases in relative disulfiram bioavailably probably resulting from saturation of the first-pass effect.
Increasing disulfiram exposure resulted in linear, significant increases in CA-US RNA (maximum effect [Emax] 60% effect half-life of 4 days, P < 0.001). For CA-US RNA, the exposure-response relationship was greatest for the M2 metabolite (diethyldithiocarbamate-methyl ester).
All study participants responded to disulfiram according to CA-US RNA analyses, but 3 participants (10%) had much higher efficacy (Emax 300%) compared with Emax predicted by pharmacokinetic estimates alone. The investigators speculated that these "enhanced responders" suggest nonpharmacologic mechanisms also play a part in the CA-US RNA response of some people to disulfiram. Disulfiram did not appear to have a significant exposure-response effect for plasma HIV RNA.
The UCSF team concluded that "disulfiram results in a linear exposure-response on increases in CA-US RNA." They speculated that higher disulfiram doses may yield even greater CA-US RNA responses. Finally, they proposed that "optimizing exposure" to specific disulfiram metabolites may be a fruitful avenue for future studies.
References
1. Lee SA, Elliott JH, McMahon J, et al. Disulfiram reactivates latent HIV infection in a dose-dependent manner. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. May 26-28, 2015. Washington, DC. Abstract 11.
2. MedlinePlus. Disulfiram. http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682602.html
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