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Prototype trial design for rapid dose selection of antiretroviral drugs: an example using emtricitabine (Coviracil).
- Source :
-
The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2001 Oct; Vol. 48 (4), pp. 507-13. - Publication Year :
- 2001
-
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.
- Subjects :
- Adult
Anti-HIV Agents pharmacokinetics
Anti-HIV Agents therapeutic use
Clinical Trials as Topic standards
Deoxycytidine pharmacokinetics
Deoxycytidine therapeutic use
Dose-Response Relationship, Drug
Emtricitabine
Female
HIV Infections virology
HIV-1 drug effects
HIV-1 physiology
Humans
Male
Reverse Transcriptase Inhibitors pharmacokinetics
Reverse Transcriptase Inhibitors therapeutic use
Viral Load
Anti-HIV Agents administration & dosage
Clinical Trials as Topic methods
Deoxycytidine administration & dosage
Deoxycytidine analogs & derivatives
HIV Infections drug therapy
Research Design standards
Reverse Transcriptase Inhibitors administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 0305-7453
- Volume :
- 48
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The Journal of antimicrobial chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 11581229
- Full Text :
- https://doi.org/10.1093/jac/48.4.507