The safety, tolerance, pharmacokinetics, and efficacy of PNU-140690, a new non-peptidic HIV protease inhibitor, in a phase I/II study.
Originally Published on February 1, 2000
Wang Y; Tutton CM; Borin MT; Daenzer CL; Li H; Wurtz RM; Piergies AA; Freimuth WW
Int Conf AIDS. 1998;12:777 (abstract no. 293/41176).
ABSTRACT: BACKGROUND: PNU-140690 is a new nonpeptidic HIV protease inhibitor (PI) effective against ritonavir/indinavir resistant HIV isolates in vitro.
METHODS: Open-label, multiple-doses (900, 1200 and 1500 mg TID) of PNU-140690 were administered to 24 PI naive patients, who had CD4 cell > 50 cells/mm3, HIV RNA > 4000 copies/mL, and were on stable dual nucleoside reverse transcriptase inhibitors (NRTIs) for > or = 2 months (median--10 months). Pharmacokinetic parameters were estimated from steady-state profiles obtained on study day 10. Primary immunological and virological parameters for efficacy were CD4 and plasma HIV-1 RNA measured by Roche's Amplicor and ultrasensitive assay.
RESULTS: Data collected up to 4 weeks showed that PNU-140690 was well tolerated. No serious adverse events (AE) reported. Primary AEs were gastrointestinal (GI) tract related including diarrhea, nausea and vomiting that were managed by taking study drug with light snacks, although 37% were treated symptomatically. Steady-state trough PNU-140690 concentrations on day 10 averaged 1.2 +/- 0.6, 1.9 +/- 1.2, and 2.8 +/- 1.6 microM in the 900, 1200, and 1500 mg TID groups, respectively. Adding PNU-140690 to dual NRTI therapy resulted in mean HIV RNA reductions of 1.0, 1.3 and 1.2 log on day 11 in the 900, 1200, and 1500 mg TID groups, respectively. At week 4 the corresponding average RNA reductions were 0.5, 1.1, and 0.9 logs in these groups. No genotypic changes observed at week 4. Clinical records suggested compliance was correlated with the changes in HIV RNA levels.
CONCLUSIONS: PNU-140690, a new nonpeptidic HIV protease inhibitor with potent antiRetroviral effect has been well tolerated in PI naive patients in
this study at doses of 900 to 1500 mg TID. There were no significant adverse effects of PNU-140690 observed when PNU-140690 was added to stable dual NRT1 therapy. The pharmacokinetics of PNU-140690 taken with two NRTIs in HIV-1 infected patients were similar to those observed in healthy volunteers receiving PNU-140690 alone.
