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Clin Ther. 1999 May;21(5):818-28.

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

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University of Pennsylvania School of Medicine, Philadelphia, USA.


This double-masked, randomized, placebo-controlled 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 QTc 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 (AUC0-infinity) exhibited dose proportionality. The maximum plasma concentration (Cmax) 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 QTc interval. Increases in the QTc interval correlated well with Cmax but not with AUC0-infinity. The time to reach Cmax showed a slight tendency to increase with dose, as did the terminal elimination half-life. Changes in QTc-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 (AUC0-infinity) was dose independent; however, the rate of absorption was dose dependent, with Cmax increasing substantially less than proportionally to the administered dose. This limited the Cmax of sparfloxacin at supratherapeutic doses and thus the increase in QTc interval. Rechallenge demonstrated that only 2 of 8 subjects had the same degree of QTc-interval prolongation, emphasizing the marked variability in the QTc interval.

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