Background

Numerous drugs have the potential to be affected by cytochrome P450 (CYP) 2B6-mediated drug–drug interactions (DDIs).

Objectives

In this work, we extend a static approach to the prediction of the extent of pharmacokinetics DDIs between substrates and inhibitors or inducers of CYP2B6.

Methods

This approach is based on the calculation of two parameters (the contribution ratio [CR], representing the fraction of dose of the substrate metabolized via this pathway and the inhibitory or inducing potency of the perpetrator [IR or IC, respectively]) calculated from the area under the concentration–time curve (AUC) ratios obtained in in-vivo DDI studies.

Results

Forty-eight studies involving 5 substrates, 11 inhibitors and 18 inducers of CYP2B6 (overall 15 inhibition and 33 induction studies) were divided into test and validation sets and considered for estimation of the parameters. The proposed approach demonstrated a fair accuracy for predicting the extent of DDI related to CYP2B6 inhibition and induction, all predictions related to the validation test (N = 18) being 50–200% of the observed ratios.

Conclusions

This methodology can be used for proposing initial dose adaptations to be adopted, for example in clinical use or for designing DDI studies involving this enzyme.

中文翻译：

---

细胞色素 P450 2B6 抑制或诱导引起的药物相互作用的定量预测

背景

许多药物都有可能受到细胞色素 P450 (CYP) 2B6 介导的药物-药物相互作用 (DDI) 的影响。

目标

在这项工作中，我们将静态方法扩展到预测 CYP2B6 的底物和抑制剂或诱导剂之间的药代动力学 DDI 程度。

方法

该方法基于计算两个参数（贡献率 [CR]，表示通过该途径代谢的底物剂量分数和肇事者的抑制或诱导效力 [IR 或 IC，分别]）计算自在体内 DDI 研究中获得的浓度 - 时间曲线下面积 (AUC) 比率。

结果

涉及 CYP2B6 的 5 种底物、11 种抑制剂和 18 种诱导剂的 48 项研究（总共 15 项抑制和 33 项诱导研究）被分为测试组和验证组，并考虑用于估计参数。所提出的方法证明了预测与 CYP2B6 抑制和诱导相关的 DDI 程度的相当准确度，所有与验证测试（N  = 18）相关的预测是观察到的比率的 50-200%。

结论

该方法可用于建议采用初始剂量调整，例如在临床使用中或用于设计涉及该酶的 DDI 研究。