A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir).
OBJECTIVE
To investigate the safety, pharmacokinetics, and activity of the orally bio-available protease inhibitor MK-639.


METHODS
An open-label Phase I/II trial of medically stable subjects with screening CD4 lymphocyte counts < or = 300 x 10(6)/I and > or = 20,000 HIV RNA copies/ml. Pharmacokinetics were performed at days 1 and 15. In order to better understand the relationships between drug exposure, baseline activity markers, and their changes during the study, mathematical modeling was performed using the traditional sigmoid-Emax relationship of pharmacologic effect and first order inhomogeneous differential equations for a two compartment system.


RESULTS
The five men enrolled had extensive prior nucleoside therapy (mean, 32.6 +/- 25.6 months), a low mean CD4 lymphocyte cell count (CD4 count, 66.1 +/- 61 x 10(6)/I and CD4 percentage, 4.4 +/- 3.1%), high soluble tumor necrosis factor-alpha type II (sTNFII) receptor concentration (6.23 +/- 2.76 ng/ml) and high viral load (5.13 +/- 0.46 log10 RNA copies/ ml; geometric mean, 133,941 copies/ml). The drug was well tolerated at a dose of 600 mg every 6 h. The steady state concentrations Cmax and Cmin were 4.94 +/- 2.16 microM and 0.28 +/-0.1 microM, respectively, which are approximately equal to 50 and 3 times the 95% inhibitory concentration (IC95) for clinical isolates, respectively. The mean increase in CD4 cell count was 143 x 10(6)/ (217% increase ), the mean increase in CD4 percentage was 5.2 percentage points (118%), mean decrease in HIV RNA was 1.55 log10 RNA copies/ml (a geometric mean difference of 130,120 copies/ml or 97% decrease) with a slow upward drift on continued therapy to a mean 0.64 log10 RNA copies/ml decrease by week 24 (a geometric mean difference of 103,084 copies/ml or 77% decrease), and a mean decrease in sTNFII receptors of 2.78 ng/ml (45% decrease). The mean CD4 counts per week as a function of the starting CD4 counts fit a sigmoid-Emax relationship (r2 = 0.998, P < 0.0001) with the return of CD4 cells being strongly related to the number of CD4 cells at baseline. Drug exposure as measured by either the total exposure (area under the concentration/time curve) or as the Cmin gave similar significant relationships to the fractional inhibition of HIV generation (r2 = 0.999, P < 0.0001, and r2 = 0.996, P < 0.0001, respectively).


CONCLUSIONS
MK-639 appears to have significant dose-related antiviral activity and is well tolerated.
Stein
D S
DS
Albany Medical College, Clinical Pharmacology Studies Unit, NY 12208, USA.
Fish
D G
DG
Bilello
J A
JA
Preston
S L
SL
Martineau
G L
GL
Drusano
G L
GL
D000328:Adult; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D019469:Indinavir; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis
D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D011725:Pyridines; D012367:RNA, Viral; D018124:Receptors, Tumor Necrosis Factor; D019469:Indinavir