Adults prescribed ETI who underwent dose reduction due to the AEs were included in this case series, and their percent predicted forced expiratory volume in 1 s (ppFEV1 ) and self-reported respiratory symptoms were collected. The full physiologically based pharmacokinetic (PBPK) models of ETI were developed incorporating physiological information and drug-dependent parameters. The models were validated against available pharmacokinetic and dose-response relationship data. The models were then used to predict lung concentrations of ETI at steady-state.
Fifteen patients underwent dose reduction in ETI due to AEs. Clinical stability without significant changes in ppFEV1 after dose reduction was observed in all patients. Resolution or improvement of AEs occurred in 13 of the 15 cases. The model-predicted lung concentrations of reduced dose ETI exceeded the reported half maximal effective concentration (EC50 ) from measurement of in vitro chloride transport, providing a hypothesis as to why therapeutic efficacy was maintained.
Albeit in a small number of patients, this study provides evidence that reduced ETI doses in pwCF who have experienced AEs may be effective. The PBPK models enable exploration of a mechanistic basis for this finding by simulating target tissue concentrations of ETI that can be compared with drug efficacy in vitro.
方法:本病例系列包括因AEs导致剂量减少的ETI处方成人,收集他们预测的1s用力呼气量(ppFEV1)和自我报告的呼吸道症状的百分比。建立了完整的基于生理的药代动力学(PBPK)模型,并结合了生理信息和药物依赖性参数。根据可用的药代动力学和剂量反应关系数据验证模型。然后使用模型来预测稳态下的ETI的肺浓度。
结果:15例患者因不良事件接受ETI剂量减少。在所有患者中观察到剂量减少后ppFEV1没有显著变化的临床稳定性。15例中有13例发生了AE的消退或改善。减少剂量ETI的模型预测的肺浓度超过了体外氯化物转运测量中报告的最大有效浓度(EC50)的一半,提供了一个假设,为什么治疗功效得以维持。
结论:尽管在少数患者中,这项研究提供的证据表明,在经历AE的pwCF中减少ETI剂量可能是有效的.PBPK模型能够通过模拟ETI的靶组织浓度来探索该发现的机理基础,所述浓度可以与体外药物功效进行比较。