期刊
JOURNAL OF BIOPHARMACEUTICAL STATISTICS
卷 22, 期 2, 页码 387-400出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/10543406.2010.539309
关键词
Exposure-response analysis; Hysteresis; ICH E14; QTc prolongation
In clinical development, thorough QT interval/corrected QT interval (QT/QTc) studies are performed to demonstrate that new investigational drugs do not change cardiac repolarization. In addition to the analysis recommended by ICH E14, exposure-response modeling has recently gained increased scientific attention. A direct concentration-QTc relationship is usually assumed with this pharmacokinetics (PK) QT analysis. Consequently, unconsidered effect delays might lead to severe bias in estimation. Although literature and the Food and Drug Administration (FDA) recommend checking for hysteresis, little guidance is given for evaluating the presence of lagged effects. Based on simulated delay scenarios, we derive a metric that allows for the detection of relevant effect delays. With this, the necessity for refined modeling of lag times can be easily recognized.
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