Population Pharmacokinetics and Pharmacodynamics of Disulfiram on Inducing Latent HIV-1 Transcription in a Phase 2b Trial

Author:

Lee, Sulggi A

Elliott, Julian H

McMahon, James

Hartogenesis, Wendy

Bumpus, Namandje N

Lifson, Jeffrey

Gorelick, Robert

Bacchetti, Peter

Deeks, Steven G

Lewin, Sharon R

Savic, Radojka M
Author Address

University of California San Francisco, Department of Medicine, Division of HIV/AIDS., Department of Infectious Diseases, Alfred Hospital and Monash University., Johns Hopkins University, Department of Pharmacology and Molecular Sciences., AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland., University of California San Francisco, Department of Epidemiology and Biostatistics., The Peter Doherty Institute for Infection and Immunity, The University of Melbourne., University of California San Francisco, Department of Bioengineering and Therapeutic Sciences.,

Abstract:

Disulfiram (DSF) was well tolerated and activated viral transcription (cell-associated unspliced [CA-US] and plasma HIV RNA) in a Phase 2 dose-escalation trial in HIV+ antiretroviral therapy (ART)-suppressed participants. Here, we investigated whether exposure to disulfiram and its metabolites predicted these changes in HIV transcription. Participants were administered 500 (N=10), 1000 (N=10), or 2000 (N=10) mg of DSF for 3 consecutive days. Disulfiram and four metabolites were measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Changes in CA-US and plasma HIV RNA were quantified by PCR and analyzed in NONMEM. A seven-compartment pharmacokinetic model demonstrated non-linear elimination kinetics. The fitted median area under the curve values (AUC0-72 ) were 3816, 8386, and 22331 mg*hr/L, respectively. Higher exposure predicted greater increases in CA-US (Emax=78%, AUC50 =1600 mcg*hr/L, P=0.013) but not plasma HIV RNA. These results provide support for further development of disulfiram as an important drug for future HIV cure strategies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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