Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 2022-09-03 , DOI: 10.1007/s40262-022-01169-4 Sarah Alrubia 1, 2 , Jialin Mao 3 , Yuan Chen 3 , Jill Barber 1 , Amin Rostami-Hodjegan 1, 4
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Backgrond and Objective
Crohn’s disease (CD) is a chronic inflammatory bowel disease that affects a wide age range. Hence, CD patients receive a variety of drugs over their life beyond those used for CD itself. The changes to the integrity of the intestine and its drug metabolising enzymes and transporters (DMETs) can alter the oral bioavailability of drugs. However, there are other changes in systems parameters determining the fate of drugs in CD, and understanding these is essential for dose adjustment in patients with CD.
Methods
The current analysis gathered all the available clinical data on the kinetics of drugs in CD (by March 2021), focusing on orally administered small molecule drugs. A meta-analysis of the systems parameters affecting oral drug pharmacokinetics was conducted. The systems information gathered on intestine, liver and blood proteins and other physiological parameters was incorporated into a physiologically based pharmacokinetic (PBPK) platform to create a virtual population of CD patients, with a view for guiding dose adjustment in the absence of clinical data in CD.
Results
There were no uniform trends in the reported changes in reported oral bioavailability. The nature of the drug as well as the formulation affected the direction and magnitude of variation in kinetics in CD patients relative to healthy volunteers. Even for the same drug, the reported changes in exposure varied, possibly due to a lack of distinction between the activity states of CD. The highest alteration was seen with S-verapamil and midazolam, 8.7- and 5.3-fold greater exposure, respectively, in active CD patients relative to healthy volunteers. Only one report was available on liver DMETs in CD, and indicated reduced CYP3A4 activity. In a number of reports, mRNA expression of DMETs in the ileum and colon of CD patients was measured, focussing on P-glycoprotein (p-gp) transporter and CYP3A4 enzyme, and showed contradictory results. No data were available on protein expression in duodenum and jejunum despite their dominant role in oral drug absorption.
Conclusion
There are currently inadequate dedicated clinical or quantitative proteomic studies in CD to enable predictive PBPK models with high confidence and adequate verification. The PBPK models for CD with the available systems parameters were able to capture the major physiological influencers and the gaps to be filled by future research. Quantification of DMETs in the intestine and the liver in CD is warranted, alongside well-defined clinical drug disposition studies with a number of index drugs as biomarkers of changes in DMETs in these patients, to avoid large-scale dedicated studies for every drug to determine the effects of disease on the drug’s metabolism and disposition and the consequential safety and therapeutic concerns.
中文翻译：
改变克罗恩病的生物利用度和药代动力学：捕获 PBPK 的系统参数以帮助预测口服药物的命运
背景和目的
克罗恩病 (CD) 是一种影响广泛年龄段的慢性炎症性肠病。因此，除了用于 CD 本身的药物外，CD 患者在其一生中接受了多种药物。肠道完整性及其药物代谢酶和转运蛋白 (DMET) 的变化可以改变药物的口服生物利用度。然而，决定药物在 CD 中命运的系统参数还有其他变化，理解这些对于 CD 患者的剂量调整至关重要。
方法
目前的分析收集了 CD 中药物动力学的所有可用临床数据（截至 2021 年 3 月），重点是口服小分子药物。对影响口服药物药代动力学的系统参数进行了荟萃分析。收集的有关肠道、肝脏和血液蛋白质以及其他生理参数的系统信息被纳入基于生理学的药代动力学 (PBPK) 平台，以创建虚拟的 CD 患者群体，以期在 CD 缺乏临床数据的情况下指导剂量调整.
结果
报告的口服生物利用度的报告变化没有统一的趋势。药物的性质以及配方影响 CD 患者相对于健康志愿者的动力学变化的方向和幅度。即使是同一种药物，所报告的暴露变化也各不相同，这可能是由于 CD 的活性状态之间缺乏区别。最高的改变见于S-维拉帕米和咪达唑仑在活动性 CD 患者中的暴露量分别是健康志愿者的 8.7 倍和 5.3 倍。只有一份关于 CD 中肝脏 DMET 的报告可用，并表明 CYP3A4 活性降低。在许多报告中，测量了 CD 患者回肠和结肠中 DMET 的 mRNA 表达，重点是 P-糖蛋白 (p-gp) 转运蛋白和 CYP3A4 酶，并显示出相互矛盾的结果。尽管它们在口服药物吸收中起主导作用，但没有关于十二指肠和空肠中蛋白质表达的数据。
结论
目前在 CD 中没有足够的专门临床或定量蛋白质组学研究来启用具有高置信度和充分验证的预测 PBPK 模型。具有可用系统参数的 CD 的 PBPK 模型能够捕获主要的生理影响因素和未来研究要填补的空白。CD 中肠道和肝脏中 DMET 的量化是必要的，同时使用许多指标药物作为这些患者 DMET 变化的生物标志物的明确定义的临床药物处置研究，以避免对每种药物进行大规模专门研究以确定疾病对药物代谢和处置的影响以及随之而来的安全性和治疗问题。
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