Combining Protease Inhibitors In HIV; 1st Data

Preliminary data from the first clinical trial using two HIV protease inhibitors in combination were presented at the XI International Conference on AIDS in Vancouver, Canada, by Bill Cameron of the University of Ottawa. The early data indicate that the combination of Abbott's Norvir (ritonavir) and Hoffmann-La Roche's Invirase (saquinavir) can produce a rapid and profound viral suppression and is well-tolerated.

Discussing the rationale behind the combination, Dr Cameron noted that out of all the PIs in late-stage development or on the market, ritonavir and saquinavir are a particularly promising combination because they have unique pharmacokinetic synergy and non-overlapping mutational resistance profiles.

All three of the currently-available PIs are inhibitors of the cytochrome P450 isozyme, and particularly CYP3A4 and CYP2D6, which are involved in the metabolism of many drugs including the PIs themselves. Ritonavir is the most potent inhibitor of this system, and it dramatically increases saquinavir levels (by 50 to 100-fold) when the drugs are given together, while its own levels are also elevated by the combination. It has a lesser effect on the other available PI, Merck & Co's indinavir. Interestingly, some patients on saquinavir are already combining the drug with grapefruit juice, which also inhibits cytochrome P450, in a bid to raise circulating levels of the drug.