February 7, 2001
With nucleosides, it is the half-life of the activated intracellular triphosphate, not the serum levels, which determine how often a drug needs to be dosed. Because of this, ddI can be dosed once daily, despite a relatively short serum half-life. Abacavir has a unique metabolic pathway among the nucleosides. It is converted into the triphosphate of carbovir, rather than abacavir, and this is the active drug. It has been difficult, if not impossible, to measure carbovir triphosphate levels up to now. That has made it difficult to predict whether abacavir might succeed as a once-a-day drug.
This paper is a collaboration between clinical researchers in Vancouver and pharmacologists at the University of Liverpool who developed a competition assay for measuring intracellular carbovir triphosphate. Six patients were studied who were taking abacavir 600mg once a day as part of a clinical trial. The calculated half-life of carbovir triphosphate was greater than 12 hours.
This provides theoretical support for using abacavir as 600mg once daily. However, clinical studies are necessary before using this dose in clinical practice. It would be very premature to switch outside of a research setting, but it provides hope that more nucleoside backbones will be available to support once-daily regimens based on non-nucleoside drugs or the new BMS drug 232262, or perhaps some of the investigational once-daily boosted protease inhibitor regimens. Given the encouraging results of Margaret Fischl's directly observed therapy trial, there is increasing excitement about once-daily therapy.
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