Macaluso Matthew, Nichols Alice I, Preskorn Sheldon H
University of Kansas School of Medicine, Wichita, Kansas (Drs Macaluso and Preskorn); Pfizer Inc, Collegeville, Pennsylvania (Dr Nichols); and Laureate Institute for Brain Research, Tulsa, Oklahoma (Dr Preskorn).
Prim Care Companion CNS Disord. 2015 Mar 19;17(2). doi: 10.4088/PCC.14r01710. eCollection 2015.
The avoidance of adverse drug-drug interactions (DDIs) is a high priority in terms of both the US Food and Drug Administration (FDA) and the individual prescriber. With this perspective in mind, this article illustrates the process for assessing the risk of a drug (example here being desvenlafaxine) causing or being the victim of DDIs, in accordance with FDA guidance.
DATA SOURCES/STUDY SELECTION: DDI studies for the serotonin-norepinephrine reuptake inhibitor desvenlafaxine conducted by the sponsor and published since 2009 are used as examples of the systematic way that the FDA requires drug developers to assess whether their new drug is either capable of causing clinically meaningful DDIs or being the victim of such DDIs. In total, 8 open-label studies tested the effects of steady-state treatment with desvenlafaxine (50-400 mg/d) on the pharmacokinetics of cytochrome (CYP) 2D6 and/or CYP 3A4 substrate drugs, or the effect of CYP 3A4 inhibition on desvenlafaxine pharmacokinetics. The potential for DDIs mediated by the P-glycoprotein (P-gp) transporter was assessed in in vitro studies using Caco-2 monolayers.
Changes in area under the plasma concentration-time curve (AUC; CYP studies) and efflux (P-gp studies) were reviewed for potential DDIs in accordance with FDA criteria.
Desvenlafaxine coadministration had minimal effect on CYP 2D6 and/or 3A4 substrates per FDA criteria. Changes in AUC indicated either no interaction (90% confidence intervals for the ratio of AUC geometric least-squares means [GM] within 80%-125%) or weak inhibition (AUC GM ratio 125% to < 200%). Coadministration with ketoconazole resulted in a weak interaction with desvenlafaxine (AUC GM ratio of 143%). Desvenlafaxine was not a substrate (efflux ratio < 2) or inhibitor (50% inhibitory drug concentration values > 250 μM) of P-gp.
A 2-step process based on FDA guidance can be used first to determine whether a pharmacokinetically mediated interaction occurs and then to assess the potential clinical significance of the DDI. In the case of the drug tested in this series of studies, the potential for clinically meaningful DDIs mediated by CYP 2D6, CYP 3A4, or P-gp was found to be low.
在美国食品药品监督管理局（FDA）和个体开处方者看来，避免不良药物相互作用（DDIs）都是高度优先事项。基于这一观点，本文根据FDA指南阐述了评估一种药物（此处以去甲文拉法辛为例）引发DDIs或成为DDIs受害者风险的过程。
数据来源/研究选择：自2009年以来由申办者开展并发表的关于5-羟色胺-去甲肾上腺素再摄取抑制剂去甲文拉法辛的DDI研究，被用作FDA要求药物研发者评估其新药是否能够引发具有临床意义的DDIs或成为此类DDIs受害者的系统方法的示例。总共8项开放标签研究测试了去甲文拉法辛（50 - 400毫克/天）稳态治疗对细胞色素（CYP）2D6和/或CYP 3A4底物药物药代动力学的影响，或CYP 3A4抑制对去甲文拉法辛药代动力学的影响。使用Caco - 2单层细胞的体外研究评估了由P - 糖蛋白（P - gp）转运体介导的DDIs可能性。
根据FDA标准，审查血浆浓度 - 时间曲线下面积（AUC；CYP研究）和外排（P - gp研究）的变化以寻找潜在的DDIs。
根据FDA标准，去甲文拉法辛合并用药对CYP 2D6和/或3A4底物的影响极小。AUC的变化表明要么无相互作用（AUC几何最小二乘法均值[GM]比值的90%置信区间在80% - 125%内）要么为弱抑制（AUC GM比值为125%至<200%）。与酮康唑合并用药导致与去甲文拉法辛存在弱相互作用（AUC GM比值为143%）。去甲文拉法辛不是P - gp的底物（外排比值<2）或抑制剂（50%抑制药物浓度值>250μM）。
基于FDA指南的两步法可首先用于确定是否发生了药代动力学介导的相互作用，然后评估DDI的潜在临床意义。在这一系列研究中所测试的药物案例中，由CYP 2D6、CYP 3A4或P - gp介导的具有临床意义的DDIs可能性较低。
