The Body PRO Covers: The 1st International AIDS Society Conference on HIV Pathogenesis and Treatment


July 9, 2001

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  • Comparison of QD Protease Inhibitors (PIs): Estimated Cmin/IC50 (IQ) After Missed Dose Shows Agenerase Advantage (Poster 352)
    Authored by Naderer O., Parks D., Rogers M., Randall, S.; Snowden, W.; Maguire, M.; Furfine, E.; GlaxoSmithKline Research Trial, North Carolina, USA

Amprenavir Shows Relative Forgiveness in Daily Dosing

The battle over which protease inhibitor (PI) has the best pharmacokinetic properties when boosted by ritonavir continues and is entering a new phase with the rush to establish superiority as a once daily (QD) regimen. Clearly, the pharmacokinetics of amprenavir (APV), saquinavir (SQV), indinavir (IDV), and lopinavir (LPV) are all improved when given with low-dose ritonavir (RTV). In a previous study, 15 subjects who switched from APV 1,200mg BID to APV 1,200mg/RTV 200mg QD maintained a viral load less than 50 copies/mL at the end of 12 weeks; however, concern regarding the use of daily dosing of PIs does and should persist given the difficult pharmacokinetic and adherence issues involved in that dosing schedule.

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:

  • APV 1,200/RTV 200 QD: IC50=29nM, protein binding 90%, apparent t1/2 at 17h resulted in IQ at 24h=9.7, 36h=5.9, 48h=3.6.

  • SQV 1,600/RTV 100 QD: IC50=6nM, protein binding 97.5%, apparent t1/2 at 5.8h resulted in IQ at 24h=3.1, 36h=0.73, 48h=0.17.

  • IDV 1,200/RTV 100 QD: IC50=44nM, protein binding 60%, apparent t1/2 at 4.3h resulted in IQ at 24h=2.5, 36h=0.37, 48h=0.05.

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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