Evaluation of the Effect of Risankizumab on the Pharmacokinetics of Cytochrome P450 Substrates in Patients with Moderately to Severely Active Ulcerative Colitis or Crohn's Disease.

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Clinical Pharmacokinetics Pub Date : 2025-01-01 Epub Date: 2024-12-21 DOI:10.1007/s40262-024-01462-4
Ronilda D'Cunha, Tofial Azam, Jasmina Kalabic, Toni Anschutz, Adi Lahat, Yinuo Pang
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引用次数: 0

Abstract

Background and objective: The objective of this study was to characterize the effects of risankizumab on the pharmacokinetics of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A substrates in patients with moderately to severely active Crohn's disease (CD) or ulcerative colitis (UC) using a cocktail approach.

Methods: Patients with CD or UC (n = 20) received single doses of probe substrates for CYP1A2 (caffeine 100 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), CYP2D6 (metoprolol 50 mg), and CYP3A (midazolam 2 mg) before and after intravenous infusions of risankizumab 1800 mg once every 4 weeks for four doses. Serial blood samples were collected for determination of concentrations of the CYP probe drugs and metabolites with and without risankizumab. Trough samples for risankizumab were collected at sparse timepoints.

Results: The point estimates and 90% confidence intervals for maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time zero to infinity (AUCinf) ratios for the CYP probe substrates administered with risankizumab versus without risankizumab were mostly within the 0.8-1.25 equivalence bounds, except for omeprazole and caffeine. While the upper 90% CI for caffeine AUCinf exceeded 1.25, the point estimate was a modest 1.13 and the Cmax ratio was well within 0.8-1.25. For omeprazole, while the lower bound of the 90% CI for AUCt (0.715) and AUCinf (0.624) extended slightly below the default equivalence limit, the exposures of its metabolite, 5-hydroxy-omeprazole, formed via CYP2C19, were comparable before and after risankizumab treatment, indicating a limited impact of risankizumab. No new safety issues were identified in this study.

Conclusion: The totality of data indicated a lack of clinically relevant impact of risankizumab on the evaluated CYP enzymes in patients with CD/UC.

Clinicaltrials: GOV: NCT04254783.

评估利桑单抗对中度至重度活动性溃疡性结肠炎或克罗恩病患者细胞色素P450底物药代动力学的影响
背景和目的:本研究的目的是通过鸡尾酒疗法来表征利桑单抗对中度至重度活动性克罗恩病(CD)或溃疡性结肠炎(UC)患者细胞色素P450 (CYP) 1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A底物药代动力学的影响。方法:CD或UC患者(n = 20)在静脉输注利桑单抗1800 mg(每4周1次,共4次)前后分别给予单剂量的CYP1A2(咖啡因100 mg)、CYP2C9(华法林10 mg)、CYP2C19(奥美拉唑20 mg)、CYP2D6(美托洛尔50 mg)和CYP3A(咪达唑仑2 mg)探测底物。收集了一系列血液样本,以测定使用和不使用利桑单抗时CYP探针药物和代谢物的浓度。在稀疏的时间点收集利桑单抗的槽样。结果:除了奥美拉唑和咖啡因外,给予利桑单抗与不给予利桑单抗的CYP探针底物的最大血浆浓度(Cmax)和血浆浓度-时间曲线下面积(AUCinf)比的点估计值和90%置信区间大部分在0.8-1.25等效范围内。虽然咖啡因AUCinf的上90% CI超过1.25,但点估计值为适度的1.13,Cmax比率在0.8-1.25之间。对于奥美拉唑,虽然AUCt(0.715)和AUCinf(0.624)的90% CI下限略低于默认等效限值,但其代谢物,通过CYP2C19形成的5-羟基奥美拉唑暴露在利桑单抗治疗前后相当,表明利桑单抗的影响有限。本研究未发现新的安全性问题。结论:总的数据表明,在CD/UC患者中,risankizumab对已评估的CYP酶缺乏临床相关的影响。临床试验:GOV: NCT04254783。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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