The Cytokine Release Syndrome and/or the Proinflammatory Cytokines as Underlying Mechanisms of Downregulation of Drug Metabolism and Drug Transport: A Systematic Review of the Clinical Pharmacokinetics of Victim Drugs of this Drug–Disease Interaction Under Different Clinical Conditions,Clinical Pharmacokinetics

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The Cytokine Release Syndrome and/or the Proinflammatory Cytokines as Underlying Mechanisms of Downregulation of Drug Metabolism and Drug Transport: A Systematic Review of the Clinical Pharmacokinetics of Victim Drugs of this Drug–Disease Interaction Under Different Clinical Conditions
Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 2022-09-05 , DOI: 10.1007/s40262-022-01173-8
Milo Gatti _{1,

2} , Federico Pea _{1,

2}

Affiliation

Background and Objective

An ever-growing body of evidence supports the impact of cytokine modulation on the patient’s phenotypic drug response. The aim of this systematic review was to analyze the clinical studies that assessed the pharmacokinetics of victim drugs of this drug–disease interaction in the presence of different scenarios of cytokine modulation in comparison with baseline conditions.

Methods

We conducted a systematic review by searching the PubMed-MEDLINE database from inception until February 2022 to retrieve prospective and/or retrospective observational studies, population pharmacokinetic studies, phase I studies, and/or case series/reports that investigated the impact of cytokine modulation on the pharmacokinetic behavior of victim drugs. Only studies providing quantitative pharmacokinetic data of victim drugs by comparing normal status versus clinical conditions with documented cytokine modulation or by assessing the influence of anti-inflammatory biological agents on metabolism and/or transport of victim drugs were included.

Results

Overall, 26 studies were included. Rheumatoid arthritis (6/26; 23.1%) and sepsis (5/26; 19.2%) were the two most frequently investigated pro-inflammatory clinical scenarios. The victim drug most frequently assessed was midazolam (14/26; 53.8%; as a probe for cytochrome P450 [CYP] 3A4). Cytokine modulation showed a moderate inhibitory effect on CYP3A4-mediated metabolism (area under the concentration–time curve increase and/or clearance decrease between 1.98-fold and 2.59-fold) and a weak-to-moderate inhibitory effect on CYP1A2, CYP2C9, and CYP2C19-mediated metabolism (in the area under the concentration–time curve increase or clearance decrease between 1.29-fold and 1.97-fold). Anti-interleukin-6 agents showed remarkable activity in counteracting downregulation of CYP3A4-mediated activity (increase in the area under the concentration–time curve between 1.75-fold and 2.56-fold).

Conclusions

Cytokine modulation may cause moderate or weak-to-moderate downregulation of metabolism/transport of victim drugs, and this may theoretically have relevant clinical consequences.

中文翻译：

细胞因子释放综合征和/或促炎细胞因子作为药物代谢和药物转运下调的潜在机制：在不同临床条件下该药物-疾病相互作用的受害者药物临床药代动力学的系统评价

背景和目标

越来越多的证据支持细胞因子调节对患者表型药物反应的影响。本系统评价的目的是分析临床研究，这些研究评估了与基线条件相比，在存在不同细胞因子调节情景的情况下，这种药物-疾病相互作用的受害药物的药代动力学。

方法

我们通过搜索从开始到 2022 年 2 月的 PubMed-MEDLINE 数据库进行了系统回顾，以检索前瞻性和/或回顾性观察研究、群体药代动力学研究、I 期研究和/或调查细胞因子调节影响的病例系列/报告受害者药物的药代动力学行为。仅包括通过比较正常状态与临床条件与记录的细胞因子调节或通过评估抗炎生物制剂对代谢和/或受害药物运输的影响来提供受害药物定量药代动力学数据的研究。

结果

总体而言，纳入了 26 项研究。类风湿性关节炎 (6/26; 23.1%) 和败血症 (5/26; 19.2%) 是两种最常研究的促炎临床情况。最常评估的受害药物是咪达唑仑（14/26；53.8%；作为细胞色素 P450 [CYP] 3A4 的探针）。细胞因子调节对 CYP3A4 介导的代谢表现出中度抑制作用（浓度-时间曲线下面积增加和/或清除率降低 1.98 倍至 2.59 倍），对 CYP1A2、CYP2C9 和CYP2C19 介导的代谢（浓度-时间曲线下面积增加或清除减少 1.29 倍至 1.97 倍）。