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Journal of Antimicrobial Chemotherapy (2001) 48, 507-513
© 2001 The British Society for Antimicrobial Chemotherapy

Prototype trial design for rapid dose selection of antiretroviral drugs: an example using emtricitabine (Coviracil)

Franck S. Rousseaua,*, James O. Kahnb, Melanie Thompsonc, Donna Mildvand, David Sheppe, Jean-Pierre Sommadossif, John Delehantyg, Jeffrey N. Simpsona, Laurene H. Wanga, Joseph B. Quinna, Charles Wakeforda and Charles van der Horsth

a Triangle Pharmaceuticals, Inc., 4611 University Drive, PO Box 50530, Durham, NC 27717-0530; b University of California, San Francisco, CA; c AIDS Research Consortium, Atlanta, GA; d Beth Israel Medical Center, New York, NY; e North Shore University Hospital, Manhasset, NY; f University of Alabama, Birmingham, AL; g Trimeris, Inc., Durham, NC; h University of North Carolina, Chapel Hill, NC, USA

Antiretroviral monotherapy for initial drug characterization risks the selection of resistant virus, yet monotherapy is the only setting where many fundamental properties of a new drug can be reliably determined. Using data on viral replication kinetics and dynamics, we designed an accelerated (14 day) open-label study of single agent emtricitabine (formerly known as FTC)—a nucleoside reverse transcriptase inhibitor—to select a dosing regimen for further therapeutic study. Five regimens (25 mg bd, 100 mg od, 200 mg od, 100 mg bd and 200 mg bd) were evaluated in HIV-1-infected subjects over a 14 day dosing period to determine the optimal dose and pharmacokinetics. Serial blood samples for virological, pharmacokinetic and intracellular FTC-triphosphate measurements were drawn frequently. A dose–response relationship for the antiviral activity of emtricitabine was established, with total daily doses of 200 mg or more producing the greatest median HIV-1 viral load suppression: 1.72–1.92 log10. Based on virological outcomes, dose–response analysis and intracellular triphosphate levels, a once-daily dose of 200 mg was selected for further long-term clinical study. Adverse events possibly related to emtricitabine were unremarkable. The antiviral activity of emtricitabine correlated well with intracellular FTC-triphosphate concentrations. This study design is a safe, useful tool for early dose selection for drugs with potent antiretroviral activity and linear pharmacokinetics.

* Corresponding author. Tel: +1-919-493-5980; Fax: +1-919-493-5925.


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