Morganroth J, Talbot G H, Dorr M B, Johnson R D, Geary W, Magner D
University of Pennsylvania School of Medicine, Philadelphia, USA.
Clin Ther. 1999 May;21(5):818-28. doi: 10.1016/s0149-2918(99)80004-6.
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.
这项双盲、随机、安慰剂对照研究在无临床相关基线心电图（ECG）异常的健康成年男性和女性志愿者中进行，以评估在高达通常治疗负荷剂量4倍的潜在过量情况下，司帕沙星的心脏耐受性界限（通过对QTc间期的影响来衡量）。23名入选志愿者在4个研究阶段中依次接受单剂量司帕沙星（400、800、1200和1600毫克），每个阶段1剂。每个阶段有6名志愿者接受安慰剂。各阶段之间间隔14天的洗脱期。在每个阶段采集系列血样和进行ECG测量，以确定司帕沙星的药代动力学和药效学特征。从零时间到无穷大的浓度-时间曲线下面积（AUC0-无穷大）呈现剂量比例关系。1200毫克和1600毫克剂量后的最大血浆浓度（Cmax）低于线性剂量关系预期的值。QTc间期的平均增加和平均最大增加情况也是如此。QTc间期的增加与Cmax相关性良好，但与AUC0-无穷大无关。达到Cmax的时间和终末消除半衰期均呈现随剂量略有增加的趋势。安慰剂接受者和司帕沙星治疗的志愿者的QTc间期离散度变化相似，且无临床意义。在超治疗剂量下，司帕沙星的吸收程度（AUC0-无穷大）与剂量无关；然而，吸收速率与剂量有关，Cmax的增加远低于给药剂量的比例。这限制了超治疗剂量下司帕沙星的Cmax，从而限制了QTc间期的增加。再激发试验表明，8名受试者中只有2名的QTc间期延长程度相同，强调了QTc间期存在显著变异性。
