Preliminary study suggests: Plasma levels of amprenavir are raised by low-dose ritonavir
Durban, South Africa -- July 11, 2000 -- Preliminary results of a study of the protease inhibitor (PI) Agenerase® (amprenavir) suggest that plasma levels of amprenavir are raised by adding a low dose of the PI ritonavir. The research was presented here today at the 13th International AIDS Conference in Durban, South Africa.
"Although these data are preliminary, the findings are consistent with other research presented earlier this year at the 7th Conference on Retroviruses and Opportunistic Infections showing that concomitant dosing of low-dose ritonavir increases levels of amprenavir in the bloodstream. Boosting anti-viral drug levels in the bloodstream is a potentially important therapeutic option for achieving treatment goals," said Lynn Smiley, vice president, HIV and Opportunistic Infections Clinical Development at Glaxo Wellcome.
In the study, therapeutic drug monitoring was conducted of Agenerase combined with low-dose ritonavir in PI-experienced patients. The effect of ritonavir on amprenavir plasma levels and the efficacy/safety of the combination were evaluated.
The study included 14 patients taking 1,200 mg of Agenerase twice a day, and 15 patients taking 600 mg of Agenerase plus 100 mg of ritonavir twice a day. The drug regimens included nucleoside reverse transcriptase inhibitors in all patients; 3 patients also were taking efavirenz, a non-nucleoside reverse transcriptase inhibitor that has been observed to decrease the concentration of amprenavir in the bloodstream. Over the course of the study, 10 patients in the group treated with Agenerase 1200 mg BID were switched to the Agenerase 600 mg plus ritonavir 100 mg BID combination. Amprenavir plasma concentrations were measured before and after drug intake.
Patients on Agenerase without ritonavir had plasma concentrations of amprenavir ranging from 20ng/ml to 3022 ng/ml. When ritonavir was added, concentrations ranged from 115 ng/ml -- 4858 ng/ml.
"Amprenavir concentrations were increased in all but 2 patients switched from Agenerase to Agenerase plus ritonavir, although there was a significant degree of variability among patients. Our results support earlier research suggesting that ritonavir is a potent CYP3A inhibitor that can lead to a significant increase in concentrations of combined protease inhibitors," said Anne-Marie Taburet, Head of Pharmacy Department, Kremlin Bicetre Hospital, Kremlin Bicetre, France.
Patients on the Agenerase 600 mg plus ritonavir 100 mg BID regimen who also were taking efavirenz had mean amprenavir concentrations above 800 ng/ml. In the switched group of patients with sensitive phenotype (n=6), the decrease in plasma viral load (pVL) after one month of Agenerase plus ritonavir averaged 2 log10copies/ml. One patient had neurological and digestive adverse effects which resolved when the dose of Agenerase was reduced.
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 widely prescribed 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.
Following is the abstract of the research presented at Durban.
Complete prescribing information for Agenerase, Ziagen, Epivir, Retrovir and Combivir follows.
For additional information on Agenerase, please go to http://www.agenerase.com
For additional information, please go to http://www.treathiv.com
00-044
Mary Faye Dark
919-483-8580