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Lopinavir: The Most Potent Protease Inhibitor

Summer 2000

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

In a season that will likely see few drug candidates appearing on the market, Abbott Laboratories' lopinavir (more commonly known as ABT-378) may be the next drug to receive approval from the U.S. Food and Drug Administration (FDA).

The current state of lopinavir research was featured in several presentations at the 7th Conference on Retroviruses and Opportunistic Infections (CROI), held January 30-February 2, 2000, in San Francisco. Based on the data currently available, the future of this new, advanced-generation protease inhibitor (PI) looks particularly encouraging.


Unprecedented Anti-HIV Activity

Lopinavir was originally developed to target HIV that had mutated and become resistant to indinavir (Crixivan) and ritonavir (Norvir). In 1997, preliminary pharmacokinetic studies revealed that this novel (new) drug not only displayed ten times the potency of ritonavir, another drug developed by Abbott, but that its potency was also vastly enhanced when lopinavir was coadministered with small quantities of ritonavir. This synergism, or enhanced effect, occurs because lopinavir and ritonavir are both processed by the P450 liver enzymes. Combining the two PIs -- in a hybrid known as ABT-378/r -- causes the body to metabolize (break down) lopinavir at a slower rate; this allows plasma levels of the drug to rise significantly, thereby increasing lopinavir's bioavailability.

Recent research indicates that a formulation of 400 mg lopinavir and 100 mg ritonavir taken twice daily is able to continuously inhibit wild-type (nonmutated) HIV by more than 30-fold. In contrast, each FDA-approved PI has a maximum 4-fold inhibitory effect, in terms of the ratio between the trough, or lowest, plasma level of the drug (known as Cmin) and the concentration of the drug needed to inhibit the growth of HIV by 50% (known as EC50).

Efficacy in Treatment-naive Persons

At this year's CROI, Roy Gulick, MD, of Cornell University presented 72-week results of an ongoing Phase II trial studying the effects of various combinations of lopinavir and ritonavir in treatment-naive persons. There were two groups in this blinded, randomized study. The 32 subjects in Group I took either a 200/100 mg or a 400/100 mg dose of ABT-378/r twice a day. The 68 subjects in Group II took either a 400/100 mg or a 400/200 mg dose of ABT-378/r twice a day. All 100 participants (4% women, 35% non-White) received the 400/100 mg combination of lopinavir/ritonavir after week 48. In addition, all subjects in both groups received standard doses of d4T (Zerit) and 3TC (Epivir), both of which are nucleoside analogs, or NRTIs.

While median baseline (pretherapy) viral load levels had been 5 log copies/mL in Group I and 4.9 log copies/mL in Group II, results at 48 weeks indicated that 83%-86% of trial subjects had undetectable viral loads (below 50 copies/mL). At 72 weeks, 25 of 27 subjects (93%) remaining in Group I, and 45 of 45 subjects (100%) remaining in Group II, had viral loads below 400 copies/mL. Median baseline CD4 cell counts were 421 cells/mm3 in Group 1 and 301 cells/mm3 in Group II.

All doses of ABT-378/r were well tolerated. Only one participant dropped out of the study because of a drug-related adverse event, whereas 12% discontinued the study for other reasons. Nausea, headache, diarrhea, and asthenia (weakness) were the most commonly reported side effects. Abnormal laboratory values of grade 3 (severe) and grade 4 (life-threatening) included increased fats (cholesterol and triglycerides) and increased ALT and AST (liver enzymes).

These data indicate that lopinavir/ritonavir in general, and the 400/100 mg twice-daily dose in particular, may offer a durable first-line treatment option for HIV positive persons who have never taken anti-HIV therapy.

Efficacy in Treatment-experienced Persons

ABT-378/r also appears to show benefit in people who have experienced viral breakthrough while using currently marketed PIs. At the 7th CROI, Steven Deeks, MD, of the University of California, San Francisco (UCSF) presented 48-week data from a study of 70 subjects who had previously taken one PI and no non-nucleoside reverse transcriptase inhibitors (NNRTIs). The distribution of previously used PIs was as follows: 44% of subjects had been treated with indinavir, 36% with nelfinavir (Viracept), 13% with saquinavir (Fortovase/Invirase), 6% with ritonavir, and 1% with amprenavir (Agenerase). Subjects had a median baseline viral load of 10,000 copies/mL. All subjects were randomized to receive a blinded ABT-378/r dose (either 400/100 mg or 400/200 mg twice daily) as well as standard doses of nevirapine (Viramune) and two NRTIs, at least one of which was new.

Both doses of ABT-378/r were well tolerated through week 48. Only three subjects discontinued the trial because of adverse events, whereas 13% discontinued the study due to other reasons. Diarrhea, nausea, and asthenia were the most commonly reported side effects. As in the study done by Dr. Gulick and colleagues, abnormal laboratory values of grades 3 and 4 included increased cholesterol, triglycerides, and liver enzymes.

In several cases, ABT-378/r acted against drug-resistant HIV. Of 55 subjects for whom full PI phenotype drug resistance data were available, 64% had greater than or equal to a 4-fold reduction in sensitivity to their previously used PIs at study entry. Nevertheless, in an as-treated analysis (i.e., not including persons who discontinued the study), 49 of 58 subjects (84%) taking ABT-378/r had viral loads below 400 copies/mL by week 48. In a stricter intent-to-treat analysis (including persons who discontinued the trial), 70% had viral loads below 400 copies/mL. Eleven persons had greater than a 4-fold reduced sensitivity to ABT-378/r itself at baseline. Interestingly, seven of these subjects were among those who had a viral load below 400 copies/mL at week 48. CD4 cell levels increased an average of 125 cells/mm3 from a median baseline of 349 cells/mm3.

Beyond Resistance

The paradox of ABT-378/r's effectiveness in vivo (in the body) despite apparent in vitro (laboratory) resistance was addressed at the 7th CROI by Dale Kempf, PhD, of Abbott Laboratories, based in Abbott Park, IL. Dr. Kempf and his research group analyzed the virologic responses of subjects in the study led by Dr. Deeks. In particular, they looked at the genotypic and/or phenotypic drug resistance data that were available for 61 of the 70 study participants at weeks 24 and 48. Dr. Kempf's group found that persons responded similarly to ABT-378/r whether or not they had HIV that was phenotypically less sensitive to lopinavir at baseline. Additionally, a greater number of PI-associated viral mutations found by genotypic analysis did not correlate with a diminished drug effect.

These results suggest that certain markers of viral resistance -- particularly the presence of genotypic resistance mutations and reductions in phenotypic sensitivity -- fail to predict the utility of ABT-378/r in people who have already been treated with PIs. According to Dr. Kempf's research group, these results "are consistent with the high, sustained plasma concentrations of [lopinavir] observed in [Dr. Deeks's] study."


All of the other FDA-approved PIs, including amprenavir, also appear to work synergistically with ritonavir. Nevertheless, lopinavir/ritonavir remains one of the most thoroughly studied and promising high-powered PI drug combinations to date. If Abbott wins approval for this amalgamated formulation, both PI-experienced and PI-naive individuals will have a formidable treatment option in their hands -- provided they have access to highly active antiretroviral therapy (HAART).

On June 1, 2000, Abbott Laboratories announced that it had submitted a new drug application (NDA) to the FDA for approval to market ABT-378/r, which is now called Kaletra. The FDA will likely give its approval by the end of this year unless unforeseen problems arise during ongoing Phase II/III trials of the drug.

Lopinavir is currently available through an early access program for persons not benefiting from standard drug therapy. The recommended dose of lopinavir/ritonavir in adults is three capsules taken twice daily with food. To counter drug-drug interactions, persons using efavirenz (Sustiva) must take four capsules of lopinavir/ritonavir twice a day. For more information, call 888-711-7193 (8:00 a.m. to 7:00 p.m. ET). Outside of North America, call 00-800-49-68-59-90.

Nicholas Cheonis is Associate Editor of BETA.

Selected Sources

Abbott Laboratories submits new drug application in the U.S. for investigational HIV therapy ABT-378/r. Abbott Laboratories Press Release. June 1, 2000.

Bartlett, J.G. and others. Report from the 7th Conference on Retroviruses and Opportunistic Infections: new drugs. The Hopkins HIV Report ( March 2000.

Deeks, S. and others. ABT-378/ritonavir (ABT-378/r) suppresses HIV RNA to <400 copies/mL in 84% of PI-experienced patients at 48 weeks. 7th Conference on Retroviruses and Opportunistic Infections. San Francisco. January 30-February 2, 2000. Abstract 532.

Gulick, R. and others. ABT-378/ritonavir (ABT-378/r) in antiretroviral naive HIV+ patients: 72 weeks. 7th CROI. Abstract 515.

Kempf, D. and others. Baseline genotype and phenotype do not predict response to ABT-378/ritonavir in PI-experienced patients at 24 and 48 weeks. 7th CROI. Abstract 731.

Back to the SFAF BETA Summer, 2000 contents page.

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.
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