The cardiac pharmacodynamics of therapeutic doses of sparfloxacin

This double-masked, randomized, placebo-controlled study assessed the cardi ac safety of sparfloxacin (as measured by the effect on corrected QT [QT(c) ] interval) at the extremes of the expected therapeutic dosage range. Ninet y healthy adult male volunteers with no clinically relevant electrocardiogr aphic (ECG) abnormalities received either placebo or 1 of 3 sparfloxacin re gimens consisting of a loading dose on day 1 followed by 3 days of daily do sing at half the loading dose (200/100 mg, 400/200 mg, or 800/400 mg). Afte r each dose, serial blood samples and ECG measurements were obtained to det ermine the pharmacokinetic and pharmacodynamic variables for sparfloxacin. Increases in the area under the plasma concentration-time curve from time 0 to 24 hours (AUC(0-24)) for each dosing interval and in the maximum concen tration (C-max) on days 1 and 4 were dose proportional. The steady-state (d ay-4) values were 6% to 16% lower than the day-1 values. At steady state, t he time to C-max ranged from 2.5 to 3.9 hours across all doses and days stu died. The half-life ranged from 18.7 to 20.3 hours. Increases in the placeb o-adjusted mean change and mean maximum change in QT(c) interval were dose related. The placebo-adjusted increases on day 1 were 9, 16, and 28 millise conds after receipt of the 200/100-mg, 400/200-mg, and 800/400-mg regimens, respectively. The corresponding increases on day 4 were 7, 12, and 26 mill iseconds. The placebo-adjusted changes in QT(c) interval also showed a line ar relationship with the AUC(0-24) and C-max of sparfloxacin. In the majori ty of volunteers (>90%), these increases were within the normal range for t he QT(c) interval (less than or equal to 460 milliseconds).