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

This double-masked, randomized, placebocontrolled study was conducted in healthy adult male and female volunteers with no clinically relevant baseline electrocardiographic (ECG) abnormalities to assess the cardiac tolerability margin of sparfloxacin (as measured by the effect on QT_c interval) under conditions of potential overdose at up to 4 times the usual therapeutic loading dose. The 23 enrolled volunteers received a sequence of single doses of sparfloxacin (400, 800, 1200, and 1600 mg), 1 dose in each of 4 study periods. Six volunteers received placebo during each period. A 14-day washout separated the periods. Serial blood samples and ECG measurements were collected in each period to determine the pharmacokinetic and pharmacodynamic characteristics of sparfloxacin. The area under the concentration-time curve from time zero to infinity (AUC_0–∞) exhibited dose proportionality. The maximum plasma concentration (C_max) after the 1200-and 1600-mg doses was lower than would be expected for a linear dose relationship. This was 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 not with AUC_0–∞. 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 sparfloxacin-treated volunteers and were of no clinical consequence. At supratherapeutic doses, the extent of sparfloxacin's absorption (AUC_0–∞) was dose independent; however, the rate of absorption was dose dependent, with C_max increasing substantially less than proportionally to the administered dose. This limited the C_max of sparfloxacin at supratherapeutic doses and thus the increase in QTC_c interval. Rechallenge demonstrated that only 2 of 8 subjects had the same degree of QT_c-interval prolongation, emphasizing the marked variability in the QT_c interval.