Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.
Cystic Fibrosis Reference Centre, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
Clin Pharmacokinet. 2020 Dec;59(12):1551-1573. doi: 10.1007/s40262-020-00932-9.
Cystic fibrosis is a lethal inherited disease that affects multiple organs. To provide optimal pharmacological treatment of comorbidities associated with cystic fibrosis, relevant alterations in pharmacokinetics must be known.
The objective of this study was to compare the pharmacokinetics of drugs between patients with cystic fibrosis and controls, based on clinical study reports published from 1999 to 2019.
Clinical studies were considered if patients with cystic fibrosis and patients without cystic fibrosis/healthy volunteers were included, a drug was administered orally/intravenously and pharmacokinetic parameters were compared.
In total, 32 clinical studies were included. Twenty-one studies reported absorption parameters. For multiple drugs, speed and/or extent of oral absorption were lower in cystic fibrosis. This phenomenon is possibly related to pathophysiological changes in the gastrointestinal tract associated with cystic fibrosis. However, a large proportion of drugs had comparable absorption kinetics. Twenty-one studies discussed volume of distribution, which was comparable between groups for most drugs. Initial differences became smaller when scaled to body composition. For some highly protein-bound drugs, inflammation-related changes in plasma proteins helped explain residual variability between cystic fibrosis and controls. Twenty-four studies elaborated on clearance, whereby higher clearances were observed in cystic fibrosis. In contrast with previously published reviews, no evidence was found for increased activities of drug-metabolising enzymes nor for up-regulation of active transport processes involved in drug disposition. In most cases, scaling clearance parameters to body composition and/or incorporating differences in plasma protein concentration accounted for these larger clearances.
There is no evidence that genetic defects causing cystic fibrosis directly lead to altered pharmacokinetics. However, co-morbidities can have a potential impact on drug absorption and disposition. Because of gastrointestinal complications, it is not advisable to extrapolate drug absorption parameters from healthy volunteers to patients with cystic fibrosis. Differences observed in the volume of distribution and clearance in patients with cystic fibrosis can potentially be explained by correcting for lean body mass.
囊性纤维化是一种致命的遗传性疾病，会影响多个器官。为了为囊性纤维化相关的合并症提供最佳的药物治疗，必须了解相关的药代动力学改变。
本研究旨在根据 1999 年至 2019 年发表的临床研究报告，比较囊性纤维化患者与对照者之间药物的药代动力学。
如果纳入了囊性纤维化患者和无囊性纤维化/健康志愿者的患者，并给予口服/静脉内药物，且比较了药代动力学参数，则纳入临床研究。
共纳入 32 项临床研究。21 项研究报告了吸收参数。对于多种药物，囊性纤维化患者的口服吸收速度和/或程度较低。这种现象可能与囊性纤维化相关的胃肠道病理生理改变有关。然而，很大一部分药物具有可比较的吸收动力学。21 项研究讨论了分布容积，对于大多数药物，组间分布容积无差异。当按身体成分进行标化时，初始差异变小。对于一些高度与蛋白结合的药物，与炎症相关的血浆蛋白变化有助于解释囊性纤维化与对照者之间的残留变异性。24 项研究详细阐述了清除率，囊性纤维化患者的清除率较高。与之前发表的综述不同，没有证据表明药物代谢酶的活性增加，也没有证据表明参与药物处置的主动转运过程上调。在大多数情况下，将清除率参数按身体成分进行标化和/或纳入血浆蛋白浓度差异，可以解释这些更高的清除率。
没有证据表明导致囊性纤维化的遗传缺陷直接导致药代动力学改变。然而，合并症可能对药物吸收和处置产生潜在影响。由于胃肠道并发症，不建议将健康志愿者的药物吸收参数外推至囊性纤维化患者。囊性纤维化患者的分布容积和清除率差异可以通过校正瘦体重来解释。
