Effect of single ascending, supratherapeutic doses of sparfloxacin on cardiac repolarization (QT(c) interval)

This double-masked, randomized, placebo-controlled study was conducted in h ealthy adult male and female volunteers with no clinically relevant baselin e electrocardiographic (ECG) abnormalities to assess the cardiac tolerabili ty margin of sparfloxacin (as measured by the effect on QT(c) interval) und er conditions of potential overdose at up to 4 times the usual therapeutic loading dose. The 23 enrolled volunteers received a sequence of single dose s of sparfloxacin (400,800, 1200, and 1600 mg), I dose in each of 4 study p eriods. Six volunteers received placebo during each period. A 14-day washou t separated the periods. Serial blood samples and ECG measurements were col lected in each period to determine the pharmacokinetic and pharmacodynamic characteristics of sparfloxacin. The area under the concentration-time curv e from time zero to infinity (AUC(0-infinity)) exhibited dose proportionali ty. The maximum plasma concentration (C-max) after the 1200- and 1600-mg do ses was lower than would be expected for a linear dose relationship. This w as also the case with the mean increase and mean maximum increase in QT(c) interval. Increases in the QT(c) interval correlated well with C-max but no t with AUC(0-infinity). The time to reach C-max showed a slight tendency to increase with dose, as did the terminal elimination half-life. Changes in QT(c) interval dispersion were similar for both placebo recipients and spar floxacin-treated volunteers and were of no clinical consequence. At suprath erapeutic doses, the extent of sparfloxacin's absorption (AUC(0-infinity)) was dose independent; however, the rate of absorption was dose dependent, w ith C-max increasing substantially less than proportionally to the administ ered dose. This limited the C-max of sparfloxacin at supratherapeutic doses and thus the increase in QT, interval. Rechallenge demonstrated that only 2 of 8 subjects had the same degree of QT(c)-interval prolongation, emphasi zing the marked variability in the QT(c) interval.