title: 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.
authors.affiliation: Triangle Pharmaceuticals, Inc., 4611 University Drive, PO Box 50530, Durham, NC 27717-0530, USA.
authors.forename: F S
authors.initials: FS
authors.lastname: Rousseau
authors.forename: J O
authors.initials: JO
authors.lastname: Kahn
authors.forename: M
authors.initials: M
authors.lastname: Thompson
authors.forename: D
authors.initials: D
authors.lastname: Mildvan
authors.forename: D
authors.initials: D
authors.lastname: Shepp
authors.forename: J P
authors.initials: JP
authors.lastname: Sommadossi
authors.forename: J
authors.initials: J
authors.lastname: Delehanty
authors.forename: J N
authors.initials: JN
authors.lastname: Simpson
authors.forename: L H
authors.initials: LH
authors.lastname: Wang
authors.forename: J B
authors.initials: JB
authors.lastname: Quinn
authors.forename: C
authors.initials: C
authors.lastname: Wakeford
authors.forename: C
authors.initials: C
authors.lastname: van der Horst
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002986:Clinical Trials as Topic / Q000379:methods* / Q000592:standards; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D012107:Research Design / Q000592:standards*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; D000068679:Emtricitabine