Sunday January 30, 3:00 pm Eastern Time
Company Press Release
SOURCE: Glaxo Wellcome
Studies Show Agenerase Levels in Bloodstream Raised
by Ritonavir
SAN FRANCISCO, Calif., Jan. 30 /PRNewswire/ -- The following release was issued
today by Glaxo Wellcome:
New studies to determine the interaction of Agenerase(TM) (amprenavir)+ritonavir (Abbott) were presented today at a major
scientific meeting in San Francisco.
These studies found that concomitant dosing of ritonavir with Agenerase causes an increase in exposure to Agenerase. In the
first of three studies, ritonavir caused 9 percent (ratio=1.09), 238 percent (ratio=3.38) and 1325 percent (ratio=14.25)
increases in the steady state peak, average and trough concentrations of Agenerase in serum, respectively. Agenerase did not
affect ritonavir pharmacokinetics.
''These data indicate that ritonavir can increase the level of amprenavir in a patient's bloodstream,'' said Brian Sadler, Clinical
Pharmacokineticist, at Glaxo Wellcome. ''They allow us to proceed farther toward the goal of simplifying HIV drug regimens.''
In this open-label, drug interaction study, 18 healthy adult volunteers (10 male and eight female) were randomized to receive
either 300 mg of ritonavir every 12 hours or 450 mg of Agenerase every 12 hours for seven days. All subjects then received
300 mg of ritonavir + 450 mg of Agenerase every 12 hours for seven days. An additional study examined 100mg of ritonavir
taken every 12 hours. Agenerase and ritonavir are both inhibitors of the HIV-1 protease. A two compartment pharmacokinetic
model included in this presentation estimated that the peak, average and trough concentrations of Agenerase for 600 mg
Agenerase + 100 mg ritonavir (BID) were: peak 4.76 microliter; average (AUC) 66.1 microliter; trough 1.99 microliter. These
exposures for 600 mg Agenerase + 100 mg ritonavir are respectively: similar to, approximately 1.7 fold, and almost six times
that observed with 1200 mg Agenerase given alone.
Of the 18 subjects in the study, seven had nausea/vomiting, nine had diarrhea and three had rashes. One of the subjects with
rash withdrew secondary to rapid progression with mucosal involvement. Five of the subjects had oral numbness while on
Agenerase+ritonavir. No oral numbness was seen when Agenerase or ritonavir was given alone. Elevations in triglycerides and
liver function tests were observed during treatment with ritonavir alone, but not with Agenerase alone. The 100 mg ritonavir
dose significantly increased Agenerase exposure in a similar manner to the effect observed in the study using 300 mg ritonavir.
Fewer adverse events and laboratory abnormalities were seen in the arm receiving the 100 mg ritonavir dose compared to the
arm receiving the 300 mg ritonavir dose. In addition, the 100 mg ritonavir dose had no effect on serum glucose levels.
Another study, presented by Judy Falloon, M.D., National Institutes of Health, assessed the pharmacokinetics of Agenerase
when combined with a second protease inhibitor with or without efavirenz (DuPont). This study included 19 protease
inhibitor-experienced, HIV-infected patients with plasma RNA>500 copies/mL. The patients were enrolled into three
open-label treatment groups. The first group was given Agenerase (1200 mg BID)+ritonavir (200 mg BID)+efavirenz (600 mg
QD). The second group was given Agenerase (1200 mg BID)+ritonavir (500 mg BID)+efavirenz (600 mg QD). The third
group was given Agenerase (1200 mg BID)+nelfinavir (Agouron) (1250 mg BID)+efavirenz (600 mg QD). All patients
received Ziagen® (abacavir sulfate). Serial plasma sampling for Agenerase concentrations was performed at steady-state on
Agenerase alone (groups 1 & 2) and with dual protease inhibitors before and after the addition of efavirenz (all groups).
The addition of ritonavir increased the average concentration of Agenerase (AUC) 2.5-fold and the trough concentration by
more than 400 percent. No difference in pharmacokinetic parameters was noted between the low- and high-dose ritonavir
regimens. Nelfinavir increased the average concentration of Agenerase (AUC) approximately 1.6-fold and trough
concentrations by 200 percent. The addition of efavirenz to the dual-protease inhibitor regimen did not alter the
pharmacokinetics of Agenerase. In this study, the regimens were generally well-tolerated.
''These studies show that the drug levels of Agenerase can be increased by ritonavir,'' said Lynn Smiley, M.D., vice president,
HIV and Opportunistic Infections Clinical Development at Glaxo Wellcome. ''At Glaxo Wellcome we understand the
difficulties for patients imposed by complex HIV drug regimens, and we are committed to simplifying those regimens.''
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, early to onset and transient in nature. The most frequently
reported adverse events were nausea, diarrhea, vomiting, rash and perioral paresthesia.
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 commercialization efforts for Agenerase with co-promotion assistance from Vertex
Pharmaceuticals.
Glaxo Wellcome is a pharmaceutical industry leader in HIV research and therapies. Glaxo Wellcome also manufactures and
markets the widely used anti-HIV medicines Combivir® (lamivudine/zidovudine), Epivir® (lamivudine) and Retrovir®
(zidovudine). The company is currently engaged in basic research programs designed to investigate new targets to treat HIV,
and is continuing efforts to study the viability of increasing access to HIV therapies in the developing world.
Complete prescribing information for Agenerase, Ziagen, Epivir, Retrovir and Combivir follows.
For additional information, please go to www.treathiv.com .
For additional information on Agenerase please go to www.agenerase.com .
For additional information on Ziagen, please go to www.ziagen.com .
SOURCE: Glaxo Wellcome |
