Stein DS, Fish DG, Chodakewitz J, Emini E, Hildebrand C, Preston SL, Martineau GL, Drusango GL; National Conference on Human Retroviruses and Related Infections.

Program Abstr Second Natl Conf Hum Retrovir Relat Infect Natl Conf Hum Retrovir Relat Infect 2nd 1995 Wash DC. 1995 Jan 29-Feb 2; 167.

Albany Medical College, Albany, NY.

We conducted an open label phase 1 trial of the orally bioavailable protease inhibitor L735524 at 600 mg q6h. The entry criteria were a CD4 count less than or equal to 300, viral RNA by PCR of greater than or equal to 20000 copies/ml and adequate renal, hepatic, and bone marrow function. Pharmacokinetics were performed at day 1 and 14 with followup weekly for the first 12 weeks and then biweekly thereafter. CD4 counts and virology were obtained every 2 weeks. The 5 subjects enrolled were homosexual males, with a mean age of 37.2 +/- 4.2y, mean of 32.6 +/- 25.6 mo of prior nucleoside therapy, and mean baselines of CD4 count 66.1 +/- 61 cells/microliter, CD4% 4.4 +/- 3.1, body weight 72.6 +/- 8.3 kg and 5.13 +/- 0.46 log 10 RNA copies/ml. The drug was well tolerated with mild and reversible changes in LFT's, primarily bilirubin, and one possibly drug-associated rash that did not recur on rechallenge. The steady state Cmax and Cmin 4.94 +/- 2.16 micromolar and 0.28 +/- 0.1 micromolar, which are approximately 50 and 3 times the CIC95 for clinical isolates. The ratio of AUC0-6 on day 15 relative to day 1 was 0.8 (range 0.32-2.43). The mean increase in CD4 cell count was 143 cells/microliter, CD4% 5.2 points (both maximal at week 14), and mean decrease in RNA of 1.52 log 10 RNA copies/ml (maximal at week 4). The mean CD4 counts/week as a function of the starting CD4 counts fit a sigmoid-Emax relationship (r2=0.99) with the return of CD4 cells being strongly related to the number of CD4 cells at baseline. The patients' weights increased an average of 3.5 kg and remained stable over the current 22 weeks of followup. L735524 appears to have significant antiviral activity and is well tolerated. Further evaluation of higher doses is ongoing.

Publication Types:

• Meeting Abstracts

Keywords:

• Antigens, CD4
• Antiviral Agents
• CD4 Lymphocyte Count
• HIV Protease Inhibitors
• Humans
• Male
• RNA, Viral
• immunology
• methods

Other ID:

• 95920634

UI: 102213583

From Meeting Abstracts