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

• Published in: Clinical therapeutics Vol. 21; no. 5; pp. 818 - 828
• Main Authors: Morganroth, Joel, Talbot, George H., Dorr, Mary B., Johnson, Robert D., Geary, William, Magner, David
• Format: Journal Article
• Language: English
• Published: Belle Mead, NJ EM Inc USA 01.05.1999; Excerpta Medica
• Subjects: Adult; Anti-Infective Agents - administration & dosage; Anti-Infective Agents - adverse effects; Anti-Infective Agents - blood; Anti-Infective Agents - pharmacokinetics; Biological and medical sciences; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug toxicity and drugs side effects treatment; electrocardiography; Electrocardiography - drug effects; Female; Fluoroquinolones; Heart - drug effects; Humans; Male; maximum plasma concentration; Medical sciences; Pharmacology. Drug treatments; Placebos; QT c interval; sparfloxacin; Toxicity: cardiovascular system; sparfloxacin; maximum plasma concentration; QT c interval; electrocardiography; Heart; Human; QT interval; Toxicity; Overdosing; Single dose; Cardiovascular disease; Normal; Antibiotic; Fluoroquinolone derivatives; Activity concentration relation; Heart disease; Electrocardiography; Sparfloxacin; Antibacterial agent; Pharmacokinetics; Quinolone derivatives
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/S0149-2918(99)80004-6

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.