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

Antiretroviral monotherapy for initial drug characterization risks the sele ction of resistant virus, yet monotherapy is the only setting where many fu ndamental properties of a new drug can be reliably determined. Using data o n viral replication kinetics and dynamics, we designed an accelerated (14 d ay) 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 1 4 day dosing period to determine the optimal dose and pharmacokinetics. Ser ial blood samples for virological, pharmacokinetic and intracellular FTC-tr i phosphate measurements were drawn frequently. A dose-response relationshi p for the antiviral activity of emtricitabine was established, with total d aily doses of 200 mg or more producing the greatest median HIV-1 viral load suppression: 1.72-1.92 log(10). Based on virological outcomes, dose-respon se analysis and intracellular triphosphate levels, a once-daily dose of 200 mg was selected for further long-term clinical study. Adverse events possi bly related to emtricitabine were unremarkable. The antiviral activity of e mtricitabine correlated well with intracellular FTC-triphosphate concentrat ions. This study design is a safe, useful too[ for early dose selection for drugs with potent antiretroviral activity and linear pharmacokinetics.