Department of Clinical Pharmacology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
Data Intelligence Department, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
J Pharmacokinet Pharmacodyn. 2021 Apr;48(2):203-211. doi: 10.1007/s10928-021-09737-0. Epub 2021 Jan 29.
Concentration-QTc (C-QTc) modeling is being increasingly used in phase 1 studies. For studies without a placebo arm (single arm studies), the scientific whitepaper by Garnett et al. ( https://doi.org/10.1007/s10928-017-9558-5 ) states that time-matched baseline adjustments may minimize the effect of diurnal variation in QTc intervals, and categorical time effects are not needed in the model. However, how diurnal variations can be accounted for when only pre-dose baselines are available is unclear. This research investigates whether including categorical time effects in the model can adjust diurnal variation in single arm studies with pre-dose baselines, where QTc prolongation is evaluated at a concentration of interest based on ΔQTc at 24 h and ΔΔQTc (a model-derived difference in ΔQTc from concentration zero). To understand the operating characteristics for the models with and without categorical time effects, simulations were conducted under various scenarios considering oncology early phase studies. When the C-QTc relationship is linear, models without categorical time effects provided biased estimates for model parameters and inflated or decreased false negative rates (FNRs) depending on the pattern of diurnal variations in QTc intervals, whereas models with categorical time effects caused no biases and controlled the FNRs. For non-linear C-QTc relationships, ΔΔQTc estimations made using the model with categorical time effects were not robust. Thus, for single arm studies where only pre-dose baselines are available, we recommend collecting QTc measurements at 24 h and estimating ΔQTc at a concentration of interest at 24 h using the C-QTc model with categorical time effects.
浓度-QTc（C-QTc）建模在 I 期研究中越来越多地被应用。对于没有安慰剂组的研究（单臂研究），Garnett 等人的科学白皮书（https://doi.org/10.1007/s10928-017-9558-5）指出，时间匹配的基线调整可能最小化 QTc 间期的昼夜变化的影响，并且模型中不需要分类时间效应。然而，当仅可获得给药前基线时，如何解释昼夜变化尚不清楚。本研究调查了在仅具有给药前基线的单臂研究中，在模型中包含分类时间效应是否可以调整 QTc 延长的昼夜变化，其中 QTc 延长是基于 24 小时的 ΔQTc 和 ΔΔQTc（浓度为零时的 ΔQTc 的模型衍生差异）来评估感兴趣的浓度。为了了解具有和不具有分类时间效应的模型的工作特性，在考虑肿瘤早期研究的各种情况下进行了模拟。当 C-QTc 关系呈线性时，不具有分类时间效应的模型会对模型参数产生有偏估计，并根据 QTc 间隔的昼夜变化模式增加或降低假阴性率（FNR），而具有分类时间效应的模型则不会产生偏差并控制 FNR。对于非线性 C-QTc 关系，使用具有分类时间效应的模型进行的 ΔΔQTc 估计并不稳健。因此，对于仅具有给药前基线的单臂研究，我们建议收集 24 小时的 QTc 测量值，并使用具有分类时间效应的 C-QTc 模型在 24 小时时估算感兴趣浓度的 ΔQTc。
