Journal article

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

CLINICAL PHARMACOLOGY & THERAPEUTICS | WILEY | Published : 2019

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 s..

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University of Melbourne Researchers

Grants

Awarded by National Institutes of Health (DARE Collaboratory)


Awarded by Foundation for AIDS Research


Awarded by National Cancer Institute, National Institutes of Health


Awarded by NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES


Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES


Awarded by NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES


Funding Acknowledgements

This work was supported in part by the National Institutes of Health (the DARE Collaboratory (U19 AI096109), S.A.L.: K23GM112526, R.M.S.: KL2TR000143) the Foundation for AIDS Research (S.G.D.: 108072--50-RGRL), and the Australian National Health and Medical Research Council (S.R.L.: Australian National Health and Medical Research Council (NHMRC) Practitioner Fellowship; J.H.E.: NHMRC Career Development Fellowship). This work was also supported in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.