According to preliminary experiments in HIV-negative volunteers, giving the protease inhibitors indinavir or saquinavir with low dose ritonavir might allow these dual PI combinations to be prescribed as once daily therapies in future. This intriguing new research was presented on the opening day of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) being held in San Francisco from September 26-29th.
The creative use of drug-drug interactions has been one of this year's key developments in the search for more tolerable anti-HIV regimens. In particular, the discovery that taking ritonavir with indinavir could not only turn the latter from a three times a day to a twice daily drug, but could also relax the need for dietary restrictions, has been important given the vogue for simplified regimens.
Ritonavir's potent effect on enzymes involved in the metabolism of indinavir, and a number of other antiretrovirals, slows down the clearance of indinavir from the body when the two are taken together. This allows for less frequent dosing. Researchers from the University Hospital Nijmegen in the Netherlands, and from Merck, have now conducted pharmacokinetic study of once daily indinavir plus ritonavir, at multiple doses, in HIV-negative volunteers.
Between them, a number of dosages have been found to result in comparable peak and trough levels to those seen when indinavir is given three times daily as a sole PI. However, at this time, it is unclear which regimen is best. Both teams agree that further study, including evaluation of their safety and effects on viral load, is warranted.
A poster presentation from Roche involved a similar assessment of so-called 'baby dose' ritonavir in combination with the soft-gel formulation of saquinavir. Again, pharmacokinetic study suggests the potential for once daily dosing, though the optimal regimen was not defined at this early stage.
Burger DM et al. Dose-finding study of a once-daily indinavir/ritonavir regimen in healthy volunteers. 39th ICAAC, San Francisco, abstract 321, 1999.
Saah A et al. Multiple-dose pharmacokinetics (PK) and tolerability of indinavir (IDV) and ritonavir (RTV) combinations in a once-daily regimen in healthy volunteers (Merck 089). 39th ICAAC, San Francisco, abstract 329, 1999.
Saag MS et al. Favorable saquinavir systemic exposure and safety of once daily administration of Fortovase (saquinavir) soft gel capsule (FTV) in combination with low dose ritonavir (RTV). 39th ICAAC, San Francisco, abstract 330, 1999.