Fiske and others from DuPont Pharma reported on DPC 083, a new second generation NNRTI. He reported that preliminary data shows a favorable PK profile in covering NNRTI double mutants. Meaning that they are hopeful that 083 will have adequate blood levels (above the IC90 for double mutants) to suppress HIV for individuals with key double NNRTI mutants. Of course, this remains to be confirmed in human studies. DPC 961, also a second generation NNRTI, was being developed by DuPont, but development has been suspended to show attention to DPC 083 due to the CNS side effects observed from 961. Dupont has two other potential NNRTI candidates but both are also on the sideline while 083 gets a close look.

Fiske reported DPC 083 is potent against the single mutant variants such as L100I and K103N, and against double substitution variants such as K103N + Y181C, K103N + V108I and K103N + P225H which are observed in nevirapine, delavirdine and efavirenz failures.

Fiske reported on a phase 1 human study in HIV uninfected individuals. Five groups of male subjects (6 active/2 placebo per cohort) received 50, 100, 200, 300 and 400 mg doses of DPC 083, and one group of female subjects received 100 mg doses of DPC 083. Two doses were administered on the first day, followed by single daily doses for the following 8 days, for a total of 10 doses. Plasma samples were collected during the dosing period and for 3 weeks thereafter. They have also experimented with up to 1600 mg single doses.

He said that the preliminary pharmacokinetics appear promising. After multiple once-daily doses, peak plasma concentrations of DPC 083 were achieved 2.5 to 4 hours after dosing. Peak to trough changes were small (ratio of approximately 1.3). DPC 083 had a very long half-life (>140 hours). The half-life for 961 is about 72 hours, and the efavirenz half-life is about 55 hours. But it appears dosing for 083 will be tested once daily. DPC 083 plasma concentrations increased during the dosing period, and steady-state had not been achieved after 10 doses. After 10 doses of ≥100 mg DPC 083, the average trough concentration (Cmin-24) exceeded the calculated protein-binding-adjusted concentration needed for 90% inhibition of wild type viruses by >172-fold, of K103N virus by >11-fold, of K103N + P225H by >1.9-fold, or K103N + V108I by >2.9-fold, and of K103N + Y181C by >1.6-fold. One double mutant which appears difficult to cover is K103N+L100I. It has been seen in 2% of efavirenz failures, mostly in people who failed efavirenz, switched to nevirapine and remained on the failing regimen for a while.

Both 961 and 083, but 083 moreso, are reportedly less protein bound than efavirenz, meaning that more free drug should be available. Theoretically, this could be a factor in potency and durability. As they did when developing efavirenz, DuPont will look at 083 distribution in tissue and semen and CSF .

The hope is that DPC 083 might be effective against NNRTI resistant virus for individuals who have failed and have resistance to NNRTI(s). Again the ultimate effectiveness of any drug, including 083, must be confirmed in human studies. In this case, individuals with various degrees of NNRTI resistance will have to be tested in studies.

A phase 2 study in HIV-infected is planned for later this year. Dosing will be based on tolerability. The goal is to avoid difficult to tolerate CNS side effects.