The cardiac pharmacodynamics of therapeutic doses of sparfloxacin.
This double-masked, randomized, placebo-controlled study assessed the cardiac safety of sparfloxacin (as measured by the effect on corrected QT [QTc] interval) at the extremes of the expected therapeutic dosage range. Ninety healthy adult male volunteers with no clinically relevant electrocardiographic (ECG) abnormalities received either placebo or 1 of 3 sparfloxacin regimens consisting of a loading dose on day 1 followed by 3 days of daily dosing at half the loading dose (200/100 mg, 400/200 mg, or 800/400 mg). After each dose, serial blood samples and ECG measurements were obtained to determine the pharmacokinetic and pharmacodynamic variables for sparfloxacin. Increases in the area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24) for each dosing interval and in the maximum concentration (Cmax) on days 1 and 4 were dose proportional. The steady-state (day-4) values were 6% to 16% lower than the day-1 values. At steady state, the time to C ranged from 2.5 to 3.9 hours across all doses and days studied. The half-life ranged from 18.7 to 20.3 hours. Increases in the placebo-adjusted mean change and mean maximum change in QTc interval were dose related. The placebo-adjusted increases on day 1 were 9, 16, and 28 milliseconds 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 milliseconds. The placebo-adjusted changes in QTc interval also showed a linear relationship with the AUC0-24 and Cmax of sparfloxacin. In the majority of volunteers (>90%), these increases were within the normal range for the QTc interval (< or = 460 milliseconds).
Morganroth
J
J
Premier Research Worldwide, Philadelphia, Pennsylvania 19103, USA.
Hunt
T
T
Dorr
M B
MB
Magner
D
D
Talbot
G H
GH
D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D024841:Fluoroquinolones; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic; D013997:Time Factors
D000890:Anti-Infective Agents; D000995:Antitubercular Agents; D024841:Fluoroquinolones; C061363:sparfloxacin