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Glucose-6-Phosphate Dehydrogenase Deficiency and Antimalarial Drug Development

Ernest Beutler^*, Stephan Duparc the G6PD Deficiency Working Group

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is relatively common in populations exposed to malaria. This deficiency appears to provide some protection from this infection, but it can also cause hemolysis after administration of some antimalarial drugs, especially primaquine. The risk of drug-induced G6PD deficiency-related hemolysis depends on a number of factors including the G6PD variant, the drug and drug dosage schedule, patient status, and disease factors. Although a great deal is known about the molecular biology of G6PD, determining the potential for drug-induced hemolysis in the clinical setting is still challenging. This report discusses the potential strategies for assessing drug-induced G6PD deficiency-related hemolytic risk preclinically and in early clinical trials. Additionally, the issues important for conducting larger clinical trials in populations in which G6PD deficiency is prevalent are examined, with a particular focus on antimalarial drug development.

Received May 1, 2007. Accepted for publication June 17, 2007.

Acknowledgments: This report is manuscript number 18617-MEM from The Scripps Research Institute and is based on a report of the G6PD Working Group meeting written by Naomi Richardson (Magenta Communications Ltd., Oxford, United Kingdom) who also assisted in the development of this manuscript. We acknowledge input from the following observers present at the G6PD Working Group meeting: Thomas Kanyok, Global Health-Infectious Diseases, Bill and Melinda Gates Foundation, Seattle, WA (formerly World Health Organization Special Programme for Research and Training in Tropical Diseases, Geneva, Switzerland at the time of the meeting); Pascal Ringwald World Health Organization-Roll Back Malaria, Geneva, Switzerland; James Veazey, U.S. Army Medical Material Development Activity, Fort Detrick, MD; Colin Ohrt, Walter Reed Army Institute of Medical Research, Silver Spring, MD; Mark Fukuda, Armed Forces Research Institute for Medical Sciences, Bangkok, Thailand; and Peter Winstanley, Liverpool University, Liverpool, United Kingdom.

Financial support: The G6PD Deficiency Working Group meeting was supported by GlaxoSmithKline. The report of the G6PD Deficiency Working Group meeting and the development of the initial outline of this paper based on that report were also funded by Glaxo-SmithKline. Support was also provided by the Stein Endowment Fund.

Disclosure: Ernest Beutler is a consultant to a number of pharmaceutical firms. Stephan Duparc is a former employee of GlaxoSmith-Kline and holds shares in this company.

^* Address correspondence to Ernest Beutler, Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM-215, 10550 Torrey Pines Road, La Jolla, CA 92037. E-mail: beutler{at}scripps.edu

Authors’ addresses: Ernest Beutler, Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM-215, 10550 Torrey Pines Road, La Jolla, CA 92037, Telephone: 619-784-8040, Fax: 619-784-2083, E-mail: beutler{at}scripps.edu. Stephan Duparc, Medicines for Malaria Venture, International Center Cointrin, 20 Route de Pré-Bois, 1215 Geneva 15, Switzerland, Telephone: 41-22-799-4070, E-mail: duparcs{at}mmv.org.

The G6PD Deficiency Working Group, in addition to the named authors, included the following participants: Ogobara Doumbo, Faculty of Medicine, University of Bamako, Bamako, Mali; Kanjaksha Ghosh, Institute of Immunohaematology, Mumbai, India; Marcus Vinicius Guimaraes de Lacerda, Tropical Medicine Foundation of Amazonas, Manaus, Brazil; Didier Lapierre, GlaxoSmithKline, Greenford, United Kingdom; Sornchai Looareesuwan (deceased), Mahidol University, Bangkok, Thailand; Zulfiqarali Premji, Muhimbili University College of Health, Dar es Salaam, Tanzania; Tom Vulliamy, Imperial College London, Hammersmith, London, United Kingdom; Christopher Whitty, London School of Hygiene and Tropical Medicine, London, United Kingdom.