Perpetrators of pharmacokinetic drug-drug interactions arising from altered cytochrome P450 activity: a criteria-based assessment
Perpetrators of pharmacokinetic drug-drug interactions arising from altered cytochrome P450 activity: a criteria-based assessment
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DOI：
10.1111/j.1365-2125.2011.03903.x
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发表时间：
2011-05-01
影响因子：
3.4
通讯作者：
Doogue, Matthew P.
中科院分区：
文献类型：
--
作者：
Polasek, Thomas M.;Lin, Frank P. Y.;Doogue, Matthew P.
中心点许多药物抑制或诱导细胞色素P450酶(CYP)导致其他药物的浓度在临床上显著变化，即持续的药代动力学药物相互作用(PK-DDIS)。列出CYP底物、抑制剂和诱导剂的中心点表很常见，但它们缺乏一致性，是根据可变质量的证据构建的。在本研究中，ADDS中心点这是第一个使用客观标准和临床药代动力学药物相互作用研究来对PK-DDIS的重要肇事者进行分类的研究。这些信息旨在为PK-DDI的临床决策提供参考。现有的CYP抑制剂和诱导剂表格在识别PK-DDI的主要肇事者方面敏感性低，阳性预测值低。Center Dot已鉴定出几种可能实施CYP介导的PK-DDiS的药物，但缺乏高质量的临床药代动力学相互作用研究。目的利用临床相关标准对CYP介导的药代动力学药物-药物相互作用(PK-DDiS)的实施者进行分类，并与类似目录进行比较。方法采用已发表的临床药代动力学相互作用研究，对CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A的抑制剂和诱导剂进行评价。这些研究是根据6名人体受试者、使用有效的体内CYP酶探针底物和临床相关剂量来选择的。根据FDA的强、中或弱分类，抑制剂被描述为强、中或弱，而诱导剂则被分类为重度(=AUC的两倍下降)或弱(AUC的两倍下降)。根据探测底物清除的双重变化，编制了一份主要肇事者目录。结果从216种候选药物(349个CYP-作恶者对，CYP-PPS)中，36个抑制剂和8个诱导剂被接受为PK-DDIS的主要作恶者，得到58个CYP-PPS。相比之下，临床版CDIT的敏感性为33%，阳性预测值为68%。199个CYP-PPS被排除为主要肇事者，92个CYP-PPS没有足够的已发表的人体药代动力学数据来进行强有力的分类。结论通过基于标准的评估，被证实或可能是CYP介导的PK-DDiS的主要犯罪者的药物数量相对较少。目前对PK-DDIS的临床决策支持与已发表的证据不一致，可以使用简单的标准来改进。
center dot Many drugs inhibit or induce cytochrome P450 enzymes (CYP) to cause clinically significant changes in the concentrations of other drugs, i.e. 'perpetrate' pharmacokinetic drug-drug interactions (PK-DDIs).center dot Tables that list the substrates, inhibitors and inducers of CYP are common, but they lack consistency and are constructed from evidence of variable quality.WHAT THIS STUDY ADDScenter dot This is the first study to catalogue important perpetrators of PK-DDIs using objective criteria and clinical pharmacokinetic drug interaction studies. This information is intended to inform clinical decisions on PK-DDIs.center dot Existing tables of CYP inhibitors and inducers have low sensitivity and low positive predictive value in identifying the major perpetrators of PK-DDIs.center dot Several drugs were identified which potentially perpetrate CYP-mediated PK-DDIs, but quality clinical pharmacokinetic interaction studies are lacking. This information may be used to inform future research.AIMSTo catalogue the perpetrators of CYP-mediated pharmacokinetic drug-drug interactions (PK-DDIs) using clinically relevant criteria, and to compare this with an analogous catalogue.METHODSCandidate inhibitors and inducers of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A ('perpetrators') were evaluated using published clinical pharmacokinetic interaction studies. Studies were selected on the basis of >= six human subjects, use of a validated in vivo probe substrate for the CYP enzyme, and clinically relevant dosing. Inhibitors were described according to the FDA classifications of strong, moderate or weak, whereas inducers were classified as major (>= twofold decrease in AUC) or weak (< twofold decrease in AUC). A catalogue of major perpetrators was constructed based on twofold changes in the clearance of probe substrates. Perpetrators in the clinical version of the Cytochromes P450 Drug Interaction Table (CDIT) were compared with the 'accepted' major perpetrators.RESULTSFrom a list of 216 candidate drugs (349 CYP-perpetrator pairs, CYP-PPs), 36 inhibitors and eight inducers were accepted as major perpetrators of PK-DDIs, resulting in 58 CYP-PPs. In comparison, the clinical version of the CDIT had a sensitivity of 33% and a positive predictive value of 68%. One hundred and ninety-nine CYP-PPs were rejected as major perpetrators, and 92 CYP-PPs had insufficient published human pharmacokinetic data for robust classification.CONCLUSIONSUsing a criteria-based assessment, the number of drugs that are proven or likely major perpetrators of CYP-mediated PK-DDIs is relatively small. Current clinical decision support on PK-DDIs is inconsistent with the published evidence and can be improved using simple criteria.