Lessons from the Ritonavir Development Program

Several key findings from the development and clinical programs with ritonavir had a major impact on the subsequent HIV protease inhibitor discovery effort, leading ultimately to the discovery of lopinavir. The first was the characterization of drug resistance during ritonavir monotherapy in phase II studies. Longitudinal assessment of plasma samples from patients who initially responded to therapy with a drop in viral load, but whose plasma HIV RNA rebounded over time, revealed the stepwise accumulation of specific mutations in the HIV protease gene. Viruses isolated from the blood of these patients displayed reduced phenotypic susceptibility to ritonavir, as well as to some other protease inhibitors. Importantly, the rate at which the mutations appeared inversely correlated with the plasma trough levels of ritonavir in different patients.21 Thus, those patients with lower drug levels experienced the evolution of drug resistance at a higher rate than those with higher drug levels. The rate at which rebound occurred also inversely correlated to the degree of suppression of viral load, indicating that ongoing replication allows the production and emergence of resistant variants.22 These key findings led to the articulation of a hypothetical pharmacokinetic-pharmacodynamic (PK/PD) model for the emergence of drug resistance to protease inhibitors. Since protease inhibitors are reversible inhibitors of HIV protease, and, in general, penetrate into and egress from cells relatively quickly (in contrast to nucleosides, which are trapped intracellularly in mono-, di-, and/or triphosphate forms), protease inhibitor trough plasma levels are likely to be reasonable temporal surrogates for minimum intracellular drug levels. If, during a dosing cycle (prior to the next dose), drug concentrations decline to a level that is incompletely suppressive, allowing significant viral replication to begin, preexisting mutants in the HIV quasispecies have a replication advantage in the presence of drug. Preferential replication of these mutants results in the accumulation of additional mutations. With reduced susceptibility to drug, these multiple mutants begin replicating at even higher drug concentrations, providing increased opportunity for the evolution and selection of even more mutations. Ultimately, combination mutants with

Plasma levels

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Periodic inadequate drug levels

Dealing With Back Pain

Dealing With Back Pain

Deal With Your Pain, Lead A Wonderful Life An Live Like A 'Normal' Person. Before I really start telling you anything about me or finding out anything about you, I want you to know that I sympathize with you. Not only is it one of the most painful experiences to have backpain. Not only is it the number one excuse for employees not coming into work. But perhaps just as significantly, it is something that I suffered from for years.

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