SCH D: Antiviral Activity of a CCR5 Receptor Antagonist
D Schurmann1, R Rouzier2, R Nougarede2, J Reynes3, G Fatkenheuer4, F Raffi5, C Michelet6, A Tarral7, C Hoffmann8, J Kiunke8, H Sprenger9, J vanLier10, A Sansone11, M Jackson11, and M Laughlin*11
1Clin. Res./Charite Hosp., Berlin, Germany; 2CentreCap, Montpellier, France; 3CHU Gui De Chauliac, Montpellier, France; 4Univ. of Cologne, Germany; 5Nantes Med. Univ., France; 6Univ. Hosp. of Rennes, France; 7Biotrial, Rennes, France; 8Univ. of Kiel, Germany; 9Univ. Hosp. Groningen, The Netherlands; 10PharmaBioResearchGroup BV, Groningen, The Netherlands; and 11SPRI, Kenilworth, NJ, USA
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 Cmax 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 Cmax 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
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.
Keywords: ccr5 receptor antagonist