Expanding Information on Nelfinavir: the Next Protease Inhibitor
Nelfinavir is a potent protease inhibitor developed by Agouron Pharmaceuticals. It has been submitted to the FDA for accelerated approval and will be marketed under the brand name "Viracept. " Presentations at the 4th Retrovirus conference summarized the results of 3 pivotal trials, confirmed a unique pattern of resistance for nelfinavir, showed preliminary data on pediatric use, and explored the pharmacology and potential for drug interactions. These studies confirmed that nelfinavir is an active drug with a favorable side effect profile, but like the other protease inhibitors, there are some pharmacologic and drug interaction issues which will require sophistication by clinicians and patients alike.
Three large clinical trials were covered in a poster (Abstract #240) and an oral presentation by Dr. Bill Powderly on behalf of the Viracept Collaborative Group (Abstract #370). Study 505 was a comparison of monotherapy with two doses of nelfinavir, 500 mg 3 times daily and 750 mg 3 times daily. One third of the patients were randomized to placebo for one month to determine the toxicity of nelfinavir alone. The two other trials compared the two doses of nelfinavir in combination with other nucleoside analogues against the nucleosides alone. Study 511 involved drug naive patients randomized to triple therapy with AZT, 3TC, nelfinavir at either dose or to AZT plus 3TC alone. Study 506 involved drug experienced patients who had never taken D4T or a protease inhibitor; these patients had somewhat more advanced disease. In light of current knowledge, this trial does not represent optimal therapy, but is very applicable to the many people who have already been on AZT, ddI and 3TC. In study 511, patients in both triple therapy arms had substantial drops in viral load out to week 24, averaging about 2.0 log10 when the standard cutoff for the bDNA assay of 500 copies/mL was used, and about 2.5 log10 with an assay cutoff of 100 copies (300 fold decrease). In the AZT/3TC arms, 80% of patients had viral loads below detection (500 copies) in the 750mg nelfinavir group compared to about 65% among those taking 500mg nelfinavir with AZT and 3TC. In an attempt to explain the difference in the response between the high dose and low dose triple therapy arms, they presented a subgroup analysis in which it appeared that the high dose arm was significantly better among patients who started with more than 100,000 copies but among those with less than 100,000 copies, the two arms were equal. Given that this is a preliminary analysis with only 6 months of data, it is too early to conclude that the 500 mg 3 times daily dose is equal to the 750 mg dose in terms of efficacy, durability of response or effect on resistance (see article on nelfinavir resistance presentation by Amy Patick).
Less details were presented for study 506, the double combination of D4T with nelfinavir. In both of the D4T plus nelfinavir groups, the initial viral load decrease was about 1.5 log10 (using the cutoff of 500 -- the lower the cutoff, the greater the possible decrease you can measure). The D4T monotherapy group had an initial drop of 0.6 log. In contrast to the triple therapy trial where viral load reductions were sustained, there was some return of viral loads on double therapy with the average reduction of 1 to 1.2 log10 at 24 weeks. This was a heavily pretreated population, and it will be important to see this analyzed in more detail.
The tolerability of nelfinavir appears to be quite good. Dosing is three times daily with food. Diarrhea or loose stools is the only consistent side effect, occuring in 16-21%, but it was reported to be readily controllable with antidiarrheal medications. Only 9 to 13% of patients stopped nelfinavir for any reason; 4% stopped for an adverse reaction, 1.6% stopped drug because of diarrhea. No clear pattern of lab abnormalities was seen.
This article was provided by TheBodyPRO.com. It is a part of the publication The 4th Conference on Retroviruses and Opportunistic Infections.