SF AIDS Fdn: BETA 10/98 -- DRUG WATCH: ABT-378 -- 2nd Gen. Protease

Published in the Bulletin of Experimental Treatments for AIDS October 1998 issue, by the San Francisco AIDS Foundation.

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DRUG WATCH: ABT-378 -- A Second Generation Protease Inhibitor from Abbott

Liz Highleyman

At the 12th World AIDS Conference in July, much attention was focused on new anti-HIV drugs and new combinations of older drugs.

One of these new drugs, currently undergoing clinical trials, is Abbott Laboratories' new "second generation" protease inhibitor ABT-378. This drug does not yet have a generic or brand name. ABT-378 is a so-called designer drug that was engineered specifically to overcome some of the problems of the currently approved protease inhibitors.

Early Results

News about ABT-378 was first reported nearly two years ago. In January 1997, at the 4th Conference on Retroviruses and Opportunistic Infections, nine abstracts were devoted to results of in vitro and animal studies of the drug. At that time, researchers reported that ABT-378 had a high bioavailability and appeared to be about ten times more potent than Abbott's approved protease inhibitor, ritonavir (see Research Notes, March 1997).

ABT-378 was designed to have activity against HIV that had developed resistance to ritonavir and indinavir. In studies to date, it appears that cross-resistance between ABT-378 and these and other protease inhibitors is low, but it has been observed.

By the time of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in September 1997, results of early pharmacokinetic studies in humans of different doses of ABT-378 were available. Interestingly, the new drug appeared to work best when used with ritonavir.

ABT-378 and Ritonavir

When taken alone, ABT-378 is eliminated from the body quite rapidly. However, because ABT-378 is metabolized by the same CP450 liver enzymes as ritonavir, co-administration of the two drugs can raise ABT-378 blood levels. Ritu Lal and colleagues from Abbott reported at ICAAC that the "area under the curve," or blood concentration of ABT-378, was increased 100-fold to 300-fold when taken with a small amount (50-300 mg) of ritonavir (see Research Notes, BETA, January 1998). This phenomenon should allow for once or twice daily dosing of ABT-378. The same effect is not apparent when ABT-378 is administered with indinavir or saquinavir.

Results from Recent Conferences

At the 5th Conference on Retroviruses and Opportunistic Infections in Chicago in February 1998, Lal presented another report on ABT-378. This data was from a study of 25 participants who received 200-600 mg of ABT-378 along with 50 or 100 mg of ritonavir. ABT-378 was well-tolerated at all doses tested. The most common side effect was diarrhea. Elevated blood fat levels were seen in some people.

At the AIDS conference in Geneva, a single late-breaker presentation was devoted to ABT-378. Anthony Japour, also from Abbott, presented preliminary interim results of a Phase II clinical trial of the safety and activity of the drug. In this trial, 32 antiretroviral-näive HIV positive participants with baseline viral loads over 5,000 copies/mL (median 100,000 copies/mL) received either 200 or 400 mg of ABT-378 twice a day in combination with 100 mg of ritonavir; 3TC and d4T were added after three weeks. At three weeks, viral load had fallen by an average of 2 logs (2,000 copies). Ninety percent of the 11 participants who had reached 24 weeks of treatment had attained an undetectable viral load (below 400 copies/mL). The median CD4 count increase was 150 cells/mm³. As with the previous trial, ABT-378 was well tolerated, with the most common side effects being diarrhea, headache, and weakness. No participants dropped out of the trial due to adverse side effects. Body shape changes were not reported, but it is too soon to know whether these will eventually occur. There were no significant differences between the two dosage arms. The study is ongoing.

Although results are still preliminary and longer-term data is needed, ABT-378 appears to be a promising new addition to the antiretroviral repertoire. If the drug can be used twice -- or better yet, once -- daily, it should make a positive contribution to improved adherence.

Liz Highleyman is Acting Editor of BETA.

James, J. ABT-378: Abbott "second generation" protease inhibitor. AIDS Treatment News 265. February 21, 1997.

Japour, A. and others. Safety and efficacy of ABT-378/ritonavir in antiretroviral-naive HIV patients: preliminary Phase II results. 12th World AIDS Conference. Geneva, Switzerland, June 28-July 3, 1998. Abstract 4/12460.

Lal, R. and others. Multiple dose safety, tolerability and pharmacokinetics of ABT-378 in combination with ritonavir. 5th Conference on Retroviruses and Opportunistic Infections. Chicago, February 1-5, 1998.

Lal, R. and others. Single dose pharmacokinetics of ABT-378 in combination with ritonavir. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Canada, September 28-October 1, 1997. Abstract I-94.

Page last updated 6 October 1998