Study assessing once daily Abacavir (ABC) in a once daily ART regimen

September 16, 2003

Chicago, Sept. 16, 2003 - Studies supporting the efficacy of a once daily (QD) antiretroviral (ART) therapy regimen and the QD dosing of Ziagen® (abacavir sulfate) (ABC) were presented here today at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

CNA30021 Studies QD Regimen

A multicenter, randomized study of HIV-infected ART naïve adults compared the virologic response of 600mg QD and 300mg twice daily (BID) regimens of abacavir (in a double-blind manner), each in combination with open-label Epivir® (lamivudine) (3TC) 300mg QD and efavirenz (EFV) 600mg QD.

The ABC QD dosing regimen provided an antiretroviral response over 48 weeks that was shown to be non-inferior to the approved ABC BID dosing regimen, according to study results.

"There are a number of antiretroviral drugs that have now received FDA approval to be dosed once a day, but because of drug interactions or food requirements, finding a combination that is 'truly' QD - with a patient taking all his ART medications at one time, once a day - has been daunting," said Doug Manion, M.D., GSK vice president of clinical development. "It has been GSK's goal to test our established drugs to determine if the data would support their use QD, providing greater flexibility for patients and physicians. Epivir is already approved to be dosed once a day and the data from the two studies being presented at ICAAC this week provide additional insight into QD dosing of Ziagen. If you add in efavirenz, which is also given once daily, a true QD regimen appears possible with patients being able to take three ART pills once a day."

In the study of 770 individuals, 66 percent in the ABC QD group versus 68 percent in the ABC BID group achieved and maintained plasma HIV-1 RNA of <50 copies>100,000 copies/mL) and a median CD4+ cell count of 262 cells/mm3. In this single study, the two regimens had similar safety profiles over the 48 weeks of randomized treatment.

The reported rate of suspected hypersensitivity to abacavir was 9 percent in the ABC QD group and 7 percent in the ABC BID group and no new safety concerns emerged as a result of ABC being administered QD.

CNA10905 Evaluates QD ABC PK

Pharmacokinetic (PK) data evaluating the use of abacavir in QD regimens also were presented at ICAAC this week. The PK of the active form of ABC, carbovir triphosphate (CBV-TP), demonstrated a long elimination half-life (geometric mean 20.6 hours) in the blood cells of patients studied, according to CNA10905 study results.

"Abacavir is a carbocyclic synthetic nucleoside analogue which, intracellularly, is converted to the active metabolite carbovir triphosphate," said Dr. Manion. "Carbovir triphosphate inhibits the activity of HIV-1 reverse transcriptase, and its half-life in the blood cells of patients is a measure of the length of time in which ABC remains active," he said. ABC is a member of the nucleoside reverse transcriptase inhibitor (NRTI) class of anti-HIV drugs.

In the study, 20 HIV-positive patients, aged 18 to 55, who were already on a stable treatment regimen that included 300mg of ABC twice daily, underwent PK sampling over a 24-hour period to characterize the PK profiles of ABC in plasma and CBV-TP in peripheral blood mononuclear cells (PBMCs). On the PK sampling day, patients took their usual regimen in the morning, but withheld their evening dose of ABC in order to better characterize the elimination of CBV-TP. All other medications in their regimens remained unchanged. Blood samples were drawn before the patients took their morning doses and at hours 2, 4, 8, 12, 16 and 24 following dose administration.

The geometric mean ABC terminal half-life in plasma was 2.59 hours; the geometric mean CBV-TP terminal half-life in PBMCs was 20.64 hours.

"The short plasma half-life of ABC and the long terminal half-life of CBV-TP in blood cells suggests that there is accumulation of one of the precursors of carbovir triphosphate within the cell," said Dr. Manion. "These findings are of interest as we continue to evaluate the use of ABC as a 600mg dose taken once a day."

Abacavir is currently approved for BID dosing and lamivudine is approved for both QD and BID dosing.

Based on these studies, CNA10905 and CNA30021, and other information, GSK is developing a co-formulation of lamivudine and abacavir that is intended for once daily dosing. This co-formulation is in late-stage clinical development.

Product Information

HIV medicines do not cure HIV infection/AIDS or prevent passing HIV to others. Ziagen Tablets and Oral Solution, in combination with other antiretroviral agents, are indicated for the treatment of HIV-1 infection. This indication is based on two controlled trials of 16 and 48 weeks duration that evaluated suppression of plasma HIV-1 RNA and changes in CD4+ cell count. At present, there are no results from controlled trials evaluating the effect of Ziagen on clinical progression of HIV. Epivir in combination with other antiretroviral agents is indicated for the treatment of HIV infection.

When used as part of a combination regimen, abacavir is a potent nucleoside reverse transcriptase inhibitor (NRTI). The most serious adverse event associated with abacavir administration is a hypersensitivity reaction occurring in approximately 5 percent of patients and which can be life threatening and has been fatal in some cases. It is characterized by fever, skin rash, fatigue and gastrointestinal symptoms, such as nausea, vomiting, diarrhea or abdominal pain. Respiratory symptoms such as dyspnea, pharyngitis or cough may also occur. The diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of acute respiratory diseases, even if alternative respiratory diagnoses (pneumonia, bronchitis, flu-like illness) are possible. Therefore, patients and healthcare professionals should also watch for respiratory symptoms such as shortness of breath, sore throat or cough.

To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity reaction, abacavir should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (e.g. acute onset respiratory disease, gastroenteritis, or reactions to other medication). Rechallenge is contraindicated after a diagnosis of hypersensitivity. Symptoms of this reaction usually occur within the first six weeks of treatment although these reactions can occur at any time during therapy. The symptoms of this reaction get progressively worse with continued treatment with abacavir, but generally resolve following permanent discontinuation of abacavir. Patients experiencing these symptoms should stop taking abacavir and contact a physician immediately. Patients experiencing this reaction must not take abacavir again as restarting the drug after a hypersensitivity reaction has resulted in cases of life-threatening and fatal reactions. When therapy with abacavir has been discontinued and reinitiation of therapy is under consideration, the reason for discontinuation should be evaluated to ensure that the patient did not have a hypersensitivity reaction. A Medication Guide and Warning Card for abacavir must be provided by pharmacists to patients with each new and refilled prescription in order to provide further information to the patient on this drug.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir, lamivudine and other antiretrovirals.

Redistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy. The causal relationship, mechanism and long-term consequences of these events are currently unknown.

Epivir should be used with caution in pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis. Patients with HIV or coinfected with HIV and hepatitis B should only receive the recommended HIV dosage of Epivir (300mg/day) and not Epivir-HBV® (100mg/day). Epivir has not been adequately studied for treatment of chronic hepatitis B in coinfected patients. Clinical and laboratory exacerbations of hepatitis B have occurred after discontinuation of lamivudine and may be severe in patients with decompensated liver disease.

The most common side effects with Ziagen are nausea, vomiting, tiredness, headache, diarrhea and loss of appetite. The most common side effects with Epivir are headache, upset stomach, tiredness, and nasal signs and symptoms.

The recommended dose of Ziagen is 300mg twice a day. The recommended dose of Epivir is 150mg twice a day or 300mg once a day.

Recombinant laboratory strains of HIV-1 (HXB2) containing multiple reverse transcriptase mutations conferring abacavir resistance exhibited cross-resistance to lamivudine, didanosine, and zalcitabine in vitro.
-end-
GlaxoSmithKline is one of the world's leading research-based pharmaceutical and healthcare companies and an industry leader in HIV research and therapies. The company is engaged in basic research programs designed to investigate new targets to treat HIV.

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