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Phase I/II Evaluation of the Prophylactic Antimalarial Activity of Pafuramidine in Healthy Volunteers Challenged with Plasmodium falciparum Sporozoites

We evaluated the causal prophylactic antimalarial activity of a single oral dose of pafuramidine (DB289), an experimental prodrug of active metabolite DB75, in a randomized, double-blind, placebo-controlled, outpatient study. Sixteen healthy volunteers were dosed and challenged in a single cohort. Subjects were randomly assigned to one of three treatment arms: 100 mg pafuramidine eight days before challenge, 100 mg pafuramidine the day before challenge, or placebo. Challenge was by the bites of Plasmodium falciparum-infected Anopheles gambiae. Malaria developed in 15 persons but did not develop in one person in the day –8 pafuramidine treatment arm. Plasma levels of DB75 were lower than expected, and as intended were too low to provide suppressive prophylaxis at the earliest appearance of erythrocytic parasites. We conclude that a single dose of 100 mg pafuramidine does not adequately protect non-immune individuals against P. falciparum and shows no clinically or statistically significant evidence of causal prophylactic activity.

Received August 18, 2008. Accepted for publication October 9, 2008.

Acknowledgments: We thank the volunteers for their interest in and persistent commitment to the study; the study team members of the Drug Development Unit and the staffs at the Investigational Pharmacy and the General Clinical Research Center for efficient, reliable, and cheerful participation; Jeannette Fanning for outstanding administrative support; Drs. Patricia Charache and Richard Moore for their support and advice; Tom Spahr, Amelia Maters, Yessika Vasquez, and the entomology team for their superb technical assistance; Dr. Paul Lietman for his service and advice as safety monitor; and Dr. Carol Olson for steadfast support and for reading the manuscript.

Financial support: This work was supported by the General Clinical Research Center, funded by the National Center for Research Resources (grant M01RR000052) and by Immtech Pharmaceuticals, Inc. (Vernon Hills, IL). Myaing M. Nyunt, for whom this study served as the major PhD thesis project, was supported by a National Institutes of Health Clinical Research Scholar Awards (K12) and the Clinical Pharmacology Training Program (T32GM066691).

^* Address correspondence to Myaing M. Nyunt, Department of International Health, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, E 5541, Baltimore, MD 21205. E-mail: mnyunt{at}jhsph.edu

Note: Supplemental Figure 1 (Relationship between alanine aminotransaminase (ALT) level and diagnosis of patent malaria) and Supplemental Table 1 (Laboratory abnormalities) appear online at www.ajtmh.org.

Authors’ addresses: Myaing M. Nyunt, Department of International Health, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, E 5541, Baltimore, MD 21205. Craig W. Hendrix, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Harvey 502, 600 North Wolfe Street, Baltimore, MD 21286. Rahul P. Bakshi and Theresa A. Shapiro, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, 301 Hunterian Building, 725 North Wolfe Street, Baltimore, MD 21286. Nirbhay Kumar, Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, E 5144, Baltimore, MD 20854.