OIII-A-4

BACKGROUND CP-X is an opioid antagonist evaluated in a thorough QT (TQT) study to investigate the potential effect of CP-X concentration on the QTc interval following repeated oral administration. METHODS This was a multiple-dose, randomized, 4-period crossover, double-blind study investigating 10 mg and 40 mg QD of CP-X and placebo on Days 1 through 7, and open-label moxifloxacin 400 mg single dose on Day 7 in 64 healthy volunteers. Plasma samples were analyzed for CP-X using solid phase extraction followed by liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) analysis. Time-matched ECG measurements and pharmacokinetic data were analyzed using NONMEM V, Level 1.1. RESULTS The QTcF-concentration relationship was characterized with a linear model that accounted for effects of placebo, sex, and study day on intercept and the effect of study day on slope. The mean (95% CI) slope describing the QTcF-concentration relationship was 0.0866 (0.0476, 0.126) msec/(ng/mL) on Day 1, which translates to mean prolongations of 1.33 msec and 6.51 msec at mean Cmax following the initial 10 mg and 40 mg doses, respectively. The mean (95% CI) slope on Day 7 was 0.0480 (0.0300, 0.0670) msec/(ng/mL), producing expected prolongations of 1.80 msec and 7.49 msec at mean steady state Cmax following multiple 10 mg and 40 mg doses. CONCLUSIONS Exposure-response modeling allowed for quantification of concentration and time-dependent changes in the QTcF interval-concentration relationship in a TQT study. Clinical Pharmacology & Therapeutics (2005) 79, P29–P29; doi: 10.1016/j.clpt.2005.12.109