BLOOD LEVELS OF FORTOVASE INCREASE WITH A MINI-DOSE OF RITONAVIR

Data Presented at the 4^th International Workshop on HIV Drug Resistance and Treatment Strategies

 NUTLEY, NJ, June 15, 2000 – Data presented suggest that blood levels of the protease inhibitor (PI) FORTOVASE^® (saquinavir) are significantly increased when FORTOVASE is taken in combination with even the smallest available capsule dose of the PI ritonavir.  Researchers believe that drug concentrations need to remain high to prevent the breakthrough of viral replication, especially in antiretroviral experienced patients.  These data were presented at the 4^th International Workshop on HIV Drug Resistance and Treatment Strategies in Siteges, Spain.

“These studies are pivotal in demonstrating that FORTOVASE differs from the other protease inhibitors when combined with a mini-dose of ritonavir.  All doses of ritonavir, even 100 mg bid, was shown to increase the level of FORTOVASE in the blood,” said Dr. Michael Kilby of the University of Alabama.  “Furthermore, this study is another indication of the potential flexibility of FORTOVASE in BID or QD dosing, although clinical studies are not yet complete.”

The pharmacokinetic data, collected from two trials in a total of 120 healthy volunteers treated for up to fourteen days with intensive pharmacokinetic and safety analysis, found that FORTOVASE concentrations are increased by even the smallest doses of ritonavir studied.  The first trial (n=64) tested FORTOVASE monotherapy or saquinavir/ritonavir (SQV/RIT) twice daily in doses of 400/400, 600/300, 600/400, 800/200, 800/300 or 800/400mg.  The second study (n=56) examined FORTOVASE monotherapy or SQV/RIT at once-daily doses of 1200/100, 1200/200, 1600/100, or 1800/100.  Based on the results of these preliminary studies, a study in patients with HIV exploring the 1600/100mg regimen is ongoing.


Other Studies—Analysis Shows Need For Standardization to Predict Drug Potency

In another study examining the trough (Cmin) and antiviral endpoints of drug concentrations in HIV patients, the authors conclude that a wide range of potential Cmin/IC50 or Cmin/IC90 ratios can be calculated for any PI or boosted PI combination.  Cmin is the lowest acceptable level of a drug in the blood that provides a therapeutic response, and the Cmin ratio is an index that reflects the ability of a drug to have a favorable therapeutic response.  The authors reviewed several pharmacokinetic parameters currently being used for evaluation of PIs and found that similar data is being examined using different measuring techniques.  As a result, they caution that reports quoting single estimates of these ratios in isolation should be treated with caution, and that a common measuring technique should be established.

 In addition, the authors concluded that standards and guidelines were lacking in reporting Cmin/IC50 or Cmin/IC90 results, which has led to possible inaccuracies in the conclusions of drug potency.  The analysis concluded that standardization needs to be applied to how data is reported, including: standardizing units, basing troughs on intent-to-treat pharmacokinetic analysis, using median or geometric mean levels, accounting for differences in intracellular accumulation, and measuring in vivo EC50 directly in treated patients wherever possible.

The most frequently reported adverse events at least possibly related to treatment with FORTOVASE and of at least moderate intensity included nausea (17.8%), diarrhea (15.6%), abdominal discomfort (13.3%) and dyspepsia (8.9%).  Do not coadminister with astemizole, terfenadine, ergot derivatives, cisapride, midazolam or triazolam, due to the potential for serious and/or life-threatening events.  Concomitant use with lovastatin or simvastatin is not recommended; caution should be exercised with other HMG-CoA reductase inhibitors metabolized by the CYP 3A4 pathway.  Exacerbation of chronic liver dysfunction has been reported in patients treated with FORTOVASE.  Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time.  There have also been reports of hyperglycemia, new onset or exacerbation of diabetes and of spontaneous bleeding in patients with hemophilia.  Please refer to the complete product information for detailed safety information for FORTOVASE.

FORTOVASE^Ò (saquinavir) is a registered trademark of HLR Technology Corporation, an affiliated company of Hoffmann-La Roche Inc.