July 9, 2001
In the latest salvo, GlaxoSmithKline researchers attempted to establish the "forgiveness" of APV/RTV daily dosing and establish that it is superior to the other available agents in that regard. They calculated the inhibitory quotient (IQ) of APV/RTV, IDV/RTV, and SQV/RTV at 24, 36, and 48 hours (h) post-dose, simulating a single missed daily dose of each of these regimens. The IC50 for each PI was obtained from PI-naive subjects and the published Cmin for each PI was numerically adjusted for protein binding. 36h and 48h post dose drug concentrations were estimated using the Cmin at 24h and the RTV-boosted t1/2 of APV, SQV and IDV, and for the sake of these calculations it was assumed that the RTV-enhanced t1/2 was maintained for the entire 48 hours post-dose.
These calculated, not measured, results are:
The conclusion of the authors is that "APV has the longest t1/2 of any currently approved PI, and the highest IQ against [wild type] HIV if and when a dose is missed." This conclusion is not necessarily correct, however, as many unconsidered factors may affect this calculated result, including protein binding and t1/2 calculations, and the response data from the other companies, as they have in the past, will surely be contradictory. At this point, using QD PI regimens remains difficult given continuing questions regarding pharmacokinetics, pill burden, side effects and toxicity, and should probably remain reserved for those patients who need it based upon some unique and pressing requirement while all of these issues are sorted out in real-life clinical trials.
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