• Poster 99: Pharmacokinetics of a Second-Generation NNRTI, DPC 083, after Multiple Oral Doses in Healthy Volunteers (Authored by W.D. Fiske, J.M. Brennan, R.R. Harrison, J.L. Jobes, M.L. Volpato, and S.G. Griffith. DuPont Pharmaceuticals Co., Newark, NJ, and Wilmington, DE)
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• Poster 102: Pharmacokinetics of a Second-Generation NNRTI, DPC 961, after Multiple Oral Doses in Healthy Volunteers (Authored by A.S. Joshi, Q.T. Jiao, D.S. Waggett, M.L. Volpato, J.L. Jobes, and S.G. Griffith. DuPont Pharmaceuticals Company, Newark, NJ, and Wilmington, DE)
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Poster 99: Pharmacokinetics of a Second-Generation NNRTI, DPC 083, after Multiple Oral Doses in Healthy Volunteers

DPC 083 is one of a number of "second generation" NNRTIs under development. All currently available NNRTIs have a major drawback: a single point mutation (typically K103N) provides high-level resistance and may render the drug relatively inactive against HIV in this setting. Several of the next-generation NNRTIs don't appear to have this weakness, and DPC 083, from the makers of efavirenz, is promising in this and other regards. It appears to be potent against single-mutant variants such as K103N and L100I, as well as some common double-mutants like K103N + Y181C, K103N + V108I, and others.

In this study, five groups of male volunteers were given varying doses of DPC 083, ranging from 50 mg to 400 mg per day. One group of female volunteers received 100 mg per day. All volunteers got two doses on the first day, then once-daily dosing as listed.

Results

1. DPC 083 has a very long "half-life" in the body (i.e., time to excrete 50% of the dose, or t-1/2). This means daily dosing should be fine. In fact, the t-1/2 ranged from 143 to 175 hours, and was longer on average in women than men.

2. After 10 doses of >100 mg of DPC 083, the average trough concentration of the drug exceeded that needed for 90% inhibition of wild-type virus by 172-fold, and of K103N virus by >11-fold. Thus, the drug seems to be about twice as potent against this critical mutant as efavirenz.

3. After 10 doses of >100 mg of DPC 083, trough concentrations exceeded that needed for 90% inhibition of several double-mutants, such as those seen in failure with efavirenz, nevirapine, and delavirdine.

DPC 083 is a highly promising compound with apparent activity against several clinically important mutation patterns commonly seen in patients failing available NNRTI therapy. For DuPont, the makers of efavirenz, this is especially good news, as they would like a second-generation drug to back up efavirenz, perhaps with fewer side effects. The company recently stopped development of another experimental NNRTI compound, DPC 961, which appeared potent, but perhaps not superior to efavirenz in overall tolerability and pharmacodynamics. DPC 083 (son of Sustiva?) seems poised to move on to larger studies fairly quickly.

Poster 102: Pharmacokinetics of a Second-Generation NNRTI, DPC 961, after Multiple Oral Doses in Healthy Volunteers

This compound, DPC 961, is an experimental NNRTI with apparent activity against some single-mutant and double-mutant strains of HIV, frequently seen in drug failure with the currently available NNRTIs. This study looked at five groups of volunteers who received daily doses of from 100 mg to 400 mg per day of DPC 961. The pharmacologic characteristics of the drug were defined. Following multiple oral doses, the drug concentration exceeded that necessary to inhibit 90% of mutant strains carrying the critical K103N, as well as several double mutants commonly seen in clinical practice with NNRTI failure.

Although these results are promising, the development of this particular compound was recently put on hold by its manufacturer, DuPont. Apparently, phase two studies indicated no particular advantage over efavirenz (also their drug) with respect to adverse events, as well as a greater potential for drug-drug interactions than was initially appreciated. The company has decided instead to proceed with a different compound, DPC 083, discussed in abstract 99.