BLOOD LEVELS OF FORTOVASE
INCREASE WITH A MINI-DOSE OF RITONAVIR
Presented at the 4th International Workshop on HIV Drug
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 4th 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.”
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.
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.
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
(saquinavir) is a registered trademark of HLR Technology Corporation, an
affiliated company of Hoffmann-La Roche Inc.