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

Abstract

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.

Population Pharmacokinetics of Emtricitabine in HIV-1-Infected Adult Patients

“…However, only 0.1% of patients with moderate renal impairment had a daily AUC lower than the threshold of maximal anti-HIV activity (10 mg · h/liter). As FTC is a well-tolerated drug, even at higher dosing levels (300 mg QD [19] or 200 mg twice a day (BID) [20]), an increase in FTC exposure for patients with moderate renal impairment receiving 200 mg QD is not expected to have major effects on the safety profile of FTC.…”

Very High Concentrations of Active Intracellular Phosphorylated Emtricitabine in Neonates (ANRS 12109 Trial, Step 2)

“…The second objective was to measure the active intracellular metabolites of FTC in neonates, as previously high intracellular phosphorylated metabolites for lamivudine triphosphate (3TC-TP) and zidovudine triphosphate (AZT-TP) during the first 2 weeks of life have been detected (7). Few data have been reported so far on FTC-TP in adults (14,17), and there are, to our knowledge, no data from neonates. In the present study, FTC-TP concentrations were measured in peripheral blood mononuclear cells (PBMCs) extracted from the cord and from neonatal plasma and compared to adult concentrations.…”

Monitoring Drug Resistance in Chronic Hepatitis B Virus (HBV)-Infected Patients during Lamivudine Therapy: Evaluation of Performance of INNO-LiPA HBV DR Assay

“…However, viral breakthrough is detected in approximately 16% to 32% of patients after 1 year of treatment (12). Newer oral nucleoside/nucleotide analogues in clinical trials, such as adefovir dipivoxil (4), entecavir (6), and emtricitabine (19,18), appear to be at least as potent as lamivudine. In vitro and in vivo studies showed that adefovir and entecavir are also effective in suppressing lamivudine-resistant HBV (8).…”