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To investigate the safety, pharmacokinetics, and activity of the orally bioavailable protease inhibitor MK-639.An open-label Phase I/II trial of medically stable subjects with screening CD4 lymphocyte counts ≤ 300×106/l and ≥ 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.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 ± 61×106/l and CD4 percentage, 4.4 ± 3.1%), high soluble tumor necrosis factor-α 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 μM and 0.28 ± 0.1 μM, respectively, which are ≈50 and 3 times the 95% inhibitory concentration (IC95) for clinical isolates, respectively. The mean increase in CD4 cell count was 143×106/l (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).MK-639 appears to have significant dose-related antiviral activity and is well tolerated.