Background:  SCH C and SCH D are orally bioavailable CCR5 receptor antagonists with potent in vitro antiviral activity. SCH D has greater in vitro potency with mean IC₉₀ values approximately 5- to 10-fold lower than SCH C. The in vivo antiviral activity of SCH C has been previously demonstrated when administered to subjects infected with HIV as monotherapy for 10 days. Mean viral load reductions when administered as 25 mg twice daily, 50 mg twice daily, and 100 mg twice daily were -0.68, -1.23, and -1.50 log₁₀, respectively. The mean C_max at steady state were approximately 135 nM, 320 nM, and 740 nM. The in vivo potency of SCH D has been evaluated in a similar study as monotherapy administered for 14 days.

Methods:  We enrolled 48 subjects chronically infected with HIV into a sequential rising dose study evaluating 0 mg, 10 mg, 25 mg, and 50 mg twice daily of SCH D for 14 days. Within each of the 3 cohorts (N = 16), 12 subjects received SCH D and 4 subjects received placebo in a randomized, blinded design. Subjects were required to have been on no antiretroviral treatment for at least 8 weeks prior to enrollment and to have a CD4⁺ cell count greater than 200/mm³. 

Results:  SCH D was safe and well tolerated. Preliminary analysis of the pharmacokinetic profiles in the 3 dose levels show mean C_max at steady state of 120 nM, 270 nM, and 525 nM for the 10 mg twice daily, 25 mg twice daily, and 50 mg twice daily dose groups, respectively. As shown, there is  a dose-related increase in antiviral effects from the 10 mg twice daily to the 25 mg twice daily and 50 mg twice daily dose group. Mean log₁₀ reductions in viral load were -1.08, -1.56, and -1.62, respectively.

Conclusions:  SCH D and SCH C both demonstrate potent in vivo antiviral effects with SCH D having greater in vitro and in vivo antiviral effects.

INSERT GRAPH

Keywords: ccr5 receptor antagonist