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

Sulggi A. Lee, Julian H. Elliott, James McMahon, Wendy Hartogenesis, Namandje N. Bumpus, Jeffrey D. Lifson, Robert J. Gorelick, Peter Bacchetti, Steven G. Deeks, Sharon R. Lewin, Radojka M. Savic

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5 Citations (Scopus)

Abstract

Disulfiram (DSF) was well tolerated and activated viral transcription (cell-associated unspliced (CA-US) and plasma human immunodeficiency virus (HIV) RNA) in a phase II dose-escalation trial in HIV+ antiretroviral therapy (ART)-suppressed participants. Here, we investigated whether exposure to DSF and its metabolites predicted these changes in HIV transcription. Participants were administered 500 (N = 10), 1,000 (N = 10), or 2,000 (N = 10) mg of DSF for 3 consecutive days. DSF and four metabolites were measured by ultraperformance liquid chromatography-tandem mass spectrometry. Changes in CA-US and plasma HIV RNA were quantified by polymerase chain reaction (PCR) and analyzed in NONMEM. A seven-compartment pharmacokinetic (PK) model demonstrated nonlinear elimination kinetics. The fitted median area under the curve values for 72 hours (AUC 0–72 ) were 3,816, 8,386, and 22,331 mg*hour/L, respectively. Higher exposure predicted greater increases in CA-US (maximum effect (E max ) = 78%, AUC 50  = 1,600 μg*hour/L, P = 0.013) but not plasma HIV RNA. These results provide support for further development of DSF as an important drug for future HIV cure strategies.

Original languageEnglish
Pages (from-to)692-702
Number of pages11
JournalClinical Pharmacology & Therapeutics
Volume105
Issue number3
DOIs
Publication statusPublished - 1 Mar 2019

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