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Study: No Significant Drug Interactions When Saquinavir/Ritonavir Co-Administered With Tenofovir

NUTLEY, N.J., April 9 /PRNewswire/ -- Roche today announced results from a study demonstrating that the new boosted dosing regimen for its protease inhibitor Invirase(R) (saquinavir 1000 mg with ritonavir 100 mg twice-daily) has no significant interactions when it is co-administered with tenofovir disoproxil fumarate (300 mg once-daily). This study was presented at the Fifth International Workshop on Clinical Pharmacology of HIV Therapy, held in Rome, April 1-3.

Boosting Invirase 1000 mg with ritonavir 100 mg twice-daily, a new dosing strategy approved by the U.S. Food and Drug Administration (FDA) for use in HIV combination regimens, achieves therapeutic drug levels of saquinavir. Roche is developing a 500 mg tablet formulation of Invirase that will cut daily pill count for the new twice-daily dosing regimen in half. A filing for the 500 mg formulation is projected for submission to the FDA for review in 2004.

"Clinical studies examining drug interactions between tenofovir and other anti-HIV drugs have shown some unexpected results -- including a decrease in levels of a protease inhibitor, which could lead to inadequate viral suppression and possible resistance, or an increase in tenofovir drug levels, which could result in tenofovir-associated toxicity. Therefore, it is important that interactions between tenofovir and each anti-HIV drug be examined on a case-by-case basis," said Dr. Malte Schutz, Medical Director, Roche. "In this study, when tenofovir was taken in combination with Invirase and ritonavir, no interactions were observed, providing reassurance to physicians that these agents can be administered together in combination regimens without the need for dose adjustment."

More About the Study (Poster 4.19)
This study enrolled 18 HIV-positive adult patients who were receiving stable antiretroviral therapy, including Invirase with ritonavir plus two nucleoside reverse transcriptase inhibitors (NRTIs), excluding tenofovir, for at least two weeks prior to the study. Any patient not receiving the Invirase formulation of saquinavir was switched to this formulation a minimum of three days before day one. (There are two formulations of saquinavir; Fortovase is a formulation that can also be taken without ritonavir, three times daily.) On day one, all patients continued their stable antiretroviral regimen. From day two through 12, 300 mg of tenofovir once daily was added to the regimen.

Pharmacokinetic samples were taken on days one, three and 14. No significant changes in any measures of tenofovir levels were observed in either the acute (day two) or chronic phases (day 13). The Cmax (maximum concentration achieved) values were 268 ng/ml and 287 ng/ml, respectively; the AUC 24h ("area under curve" or time curve from zero to 24 hours) values were 2733 ng.h/ml and 3005 ng.h/ml, respectively; and the Ctrough (trough concentration) values were 56 ng/ml and 64 ng/ml, respectively. Mean saquinavir levels were similar before the addition of tenofovir and in both the acute and chronic phases after addition of tenofovir.

There were no significant differences in laboratory safety parameters, including ALT, AST, phosphorus, total cholesterol and triglycerides, and no serious adverse events or withdrawals reported in this study over 13 days.

Dosing of Boosted Invirase
The FDA approved dosing for boosted Invirase is 1000 mg of Invirase (five 200 mg capsules) in combination with ritonavir 100 mg, twice a day. Ritonavir should be taken at the same time as Invirase. Invirase and ritonavir should be taken within 2 hours after a meal.

Indication and Safety Information
Invirase capsules (saquinavir mesylate) in combination with ritonavir and other antiretroviral agents is indicated for the treatment of HIV infection (1000 mg saquinavir mesylate with 100 mg ritonavir). The twice daily administration of Invirase in combination with ritonavir is supported by safety data from the MaxCmin 1 study and pharmacokinetic data. The efficacy of Invirase with ritonavir or Fortovase (with or without ritonavir coadministration) has not been compared against the efficacy of antiretroviral regimens currently considered standard of care.

Invirase capsules and Fortovase soft gelatin capsules are not bioequivalent and cannot be used interchangeably. Invirase may be used only if it is combined with ritonavir, which significantly inhibits saquinavir's metabolism to provide plasma saquinavir levels at least equal to those achieved with Fortovase. When using saquinavir as the sole protease inhibitor in an antiviral regimen, Fortovase is the recommended formulation.

Invirase should not be administered concurrently with terfenadine, cisapride, astemizole, pimozide, triazolam, midazolam, ergot derivatives, rifampin or antiarrhymic medications, which include amiodarone, bepridil, flecainide, propafenone, and quinidine. Inhibition of CYP3A4 by saquinavir could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions, such as cardiac arrhythmias or prolonged sedation.

Concomitant use of Invirase with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including Invirase, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (eg, atorvastatin). Concomitant use of Invirase and St. John's wort (hypericum perforatum) or products containing St. John's wort is not recommended. Garlic capsules should not be used while taking saquinavir as the sole protease inhibitor due to the risk of decreased saquinavir plasma concentrations. No data are available for the coadministration of Invirase/ritonavir and garlic capsules.

New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy.

The recommended dose of Invirase and ritonavir is 1000 mg Invirase plus 100 mg ritonavir twice-daily. Coadministration of saquinavir and ritonavir has led to severe adverse events, mainly diabetic ketoacidosis and liver disorders, especially in patients with pre-existing liver disease. Invirase when administered with ritonavir is contraindicated in patients with severe hepatic impairment. Caution should be exercised when Invirase in combination with ritonavir is used by patients with hepatic impairment. Patients with severe renal impairment have not been studied and caution should be exercised when prescribing Invirase in combination with ritonavir. There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors.

Elevated cholesterol and/or triglyceride levels have been observed in some patients taking saquinavir in combination with ritonavir. Marked elevation in triglyceride levels is a risk factor for development of pancreatitis. Cholesterol and triglyceride levels should be monitored prior to initiating combination dosing regimen of Fortovase or Invirase with ritonavir, and at periodic intervals while on such therapy. In these patients, lipid disorders should be managed as clinically appropriate.

Redistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy. A causal relationship between protease- inhibitor therapy and these events has not been established and the long-term consequences are currently unknown.

The following grade 2 to grade 4 adverse events, (considered at least possibly related to study drug or of unknown relationship) occurred in at least two percent of patients receiving Invirase 600 mg tid alone or in combination with zidovudine and/or HIVID: abdominal discomfort, abdominal pain, appetite disturbances, asthenia, buccal mucosa ulceration, diarrhea, dizziness, dyspepsia, extremity numbness, headache, mucosa damage, musculoskeletal pain, myalgia, nausea, paresthesia, peripheral neuropathy, pruritus, and rash.

The following grade 2 to grade 4 adverse events (all causality) occurred in at least two percent of patients receiving Fortovase with ritonavir (1000/100 mg twice daily): abdominal pain, back pain, bronchitis, constipation, diabetes mellitus/hyperglycemia, diarrhea, dry lips/skin, eczema, fatigue, fever, influenza, lipodystrophy, nausea, pneumonia, pruritis, rash, sinusitis, and vomiting.

Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of Invirase therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.

Invirase is not a cure for HIV infection or AIDS. Invirase does not prevent the transmission of HIV.

Source: Roche

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