A study that evaluated dosage adjustments of the protease inhibitor (PI) Agenerase® (amprenavir) capsules in HIV patients treated with efavirenz or nevirapine, antiretroviral (ART) agents known to affect the plasma levels of amprenavir, was presented here today at the 40th annual meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).
A total of 86 PI-experienced patients received Agenerase in combination with efavirenz or nevirapine with treatment based on phenotypic or genotypic resistance testing. Efavirenz and nevirapine are non-nucleoside reverse transcriptase inhibitors (NNRTIs) that have been shown to affect plasma levels of amprenavir.
"When low doses of ritonavir were added to the treatment regimen of PI-experienced patients taking efavirenz or nevirapine, preliminary data from this study showed that therapeutic plasma concentrations of amprenavir were maintained at 6 or 12 weeks," said G. Peytavin, X. Bichat-Cl. Bernard Hospital, Paris, France, principal author of the study.
Plasma concentrations (Cmin) of the treatment compounds were determined at two weeks after initiation of treatment and at week 6 or 12. When Cmin of amprenavir fell below therapeutic levels (100 ng/ml), patients’ physicians were offered a choice of two dosage regimens: Agenerase 600 mg twice a day plus 100 mg of ritonavir twice-a-day, or 1200 mg of Agenerase three times a day.
At week two, 70 percent (60/86) of patients -- 87 percent (52/60) of whom were in the group treated with efavirenz -- had Cmin of amprenavir below 100 ng/ml. Dosage adjustments of Agenerase were proposed for all 60 patients. The recommendations were carried out by the physician in 50 percent (30/60) of patients at week 6 or 12. Of patients that received a dose adjustment, 93 percent (28/30) received the Agenerase plus ritonavir combination. The Cmin of amprenavir rose above 100 ng/ml in all cases, despite the presence of efavirenz or nevirapine. Plasma concentration was 2.7 ±; 2.0 mg/l (186) for efavirenz and 5.9 ±; 4.4 mg/l (46) for nevirapine.
"These preliminary data provide new information about the potential for maintaining therapeutic plasma levels of amprenavir in the presence of other antiretrovirals known to induce metabolism of amprenavir," said Lynn Smiley, M.D., vice president, HIV and Opportunistic Infections Clinical Development at Glaxo Wellcome.
Agenerase in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts in controlled studies up to 24 weeks in duration. At present, no results from controlled trials evaluating long-term suppression of HIV RNA or disease progression with Agenerase have been submitted to the FDA for evaluation.
The safety of Agenerase was studied in 736 adult patients. In patients receiving protease inhibitors, diabetes mellitus, hyperglycemia, acute hemolytic anemia and redistribution/ accumulation of fat have been reported.
Severe and life-threatening drug interactions could be associated with therapy with Agenerase (see full prescribing information for specific drug interactions). Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, have been associated with Agenerase. There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors.
The majority of adverse events were of mild to moderate intensity (grade 1-2), early to onset and transient. Treatment-limiting (grade 3-4) adverse events occurred in 5 percent or less of patients. The most frequently reported adverse events in grades 2-4 (grades 1-4 included parenthetically) were up to 31 percent nausea (73 percent), 22 percent diarrhea (56 percent), 11 percent vomiting (29 percent), 20 percent rash (25 percent) and 2 percent perioral paresthesia (30 percent). Because of the potential risk of toxicity from the large amount of the excipient propylene glycol contained in Agenerase Oral Solution, that formulation is contraindicated in certain patient populations and should be used with caution in others.
Agenerase was discovered by scientists at Vertex Pharmaceuticals of Cambridge, MA. Glaxo Wellcome has been responsible for product formulation and manufacture of Agenerase, design and implementation of clinical trials, and regulatory submissions to the FDA. Glaxo Wellcome also leads the marketing efforts for Agenerase with co-promotion assistance from Vertex Pharmaceuticals.
Glaxo Wellcome is a pharmaceutical industry leader in HIV research and therapies. In addition to Agenerase, Glaxo Wellcome also manufactures and markets the anti-HIV drugs Combivir® (lamivudine/zidovudine), Epivir® (lamivudine), Retrovir® (zidovudine) and Ziagen® (abacavir sulfate). The company is engaged in basic research programs designed to investigate new targets to treat HIV.
Complete prescribing information for Agenerase is available at http://www.agenerase.com .
For additional information, please go to http://www.combivir.com , http://www.epivir.com , http://www.agenerase.com .