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酮康唑与甲磺酸伊马替尼(格列卫)在健康受试者中的药代动力学相互作用。

Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects.

作者信息

Dutreix Catherine, Peng Bin, Mehring Guenther, Hayes Michael, Capdeville Renaud, Pokorny Rolf, Seiberling Michael

机构信息

Novartis Pharma AG, 4002 Basel, Switzerland.

出版信息

Cancer Chemother Pharmacol. 2004 Oct;54(4):290-4. doi: 10.1007/s00280-004-0832-z. Epub 2004 May 8.

Abstract

The study under discussion was a drug-drug interaction study in which the effect of ketoconazole, a potent CYP450 3A4 inhibitor, on the pharmacokinetics of Glivec (imatinib) was investigated. A total of 14 healthy subjects (13 male, 1 female) were enrolled in this study. Each subject received a single oral dose of imatinib 200 mg alone, and a single oral dose of imatinib 200 mg coadministered with a single oral dose of ketoconazole 400 mg according to a two-period crossover design. The treatment sequence was randomly allocated. Subtherapeutic imatinib doses and a short exposure were tested in order not to overexpose the healthy volunteers. There was a minimum 7-day washout period between the two sequences. Blood samples for determination of plasma concentrations were taken up to 96 h after dosing. Imatinib and CGP74588 (main metabolite of imatinib) concentrations were measured using LC/MS/MS method and pharmacokinetic parameters were estimated by a non-compartmental analysis. Following ketoconazole coadministration, the mean imatinib C(max), AUC((0-24)) and AUC((0- infinity )) increased significantly by 26% ( P<0.005), 40% ( P<0.0005) and 40% ( P <0.0005), respectively. There was a statistically significant decrease in apparent clearance (CL/f) of imatinib with a mean reduction of 28.6% ( P<0.0005). The mean C(max) and AUC((0-24)) of the metabolite CGP74588 decreased significantly by 22.6% ( P<0.005) and 13% ( P<0.05) after ketoconazole treatment, although the AUC((0- infinity )) of CGP74588 only decreased by 5% ( P=0.28). Coadministration of ketoconazole and imatinib caused a 40% increase in exposure to imatinib in healthy volunteers. Given its previously demonstrated safety profile, this increased exposure to imatinib is likely to be clinically significant only at high doses. This interaction should be considered when administering inhibitors of the CYP3A family in combination with imatinib.

摘要

正在讨论的这项研究是一项药物相互作用研究,旨在探究强效CYP450 3A4抑制剂酮康唑对格列卫(伊马替尼)药代动力学的影响。该研究共纳入了14名健康受试者(13名男性,1名女性)。按照两周期交叉设计,每位受试者单独口服一次200 mg伊马替尼,以及与单次口服400 mg酮康唑联合服用一次200 mg伊马替尼。治疗顺序随机分配。为避免使健康志愿者过度暴露,采用了低于治疗剂量的伊马替尼并进行了短时间暴露测试。两个治疗序列之间至少有7天的洗脱期。给药后长达96小时采集血样以测定血浆浓度。使用液相色谱-串联质谱法(LC/MS/MS)测定伊马替尼和CGP74588(伊马替尼的主要代谢产物)的浓度,并通过非房室分析估算药代动力学参数。酮康唑联合给药后,伊马替尼的平均C(max)、AUC((0 - 24))和AUC((0 - ∞))分别显著增加了26%(P < 0.005)、40%(P < 0.0005)和40%(P < 0.0005)。伊马替尼的表观清除率(CL/f)有统计学意义的下降,平均降低了28.6%(P < 0.0005)。酮康唑治疗后,代谢产物CGP74588的平均C(max)和AUC((0 - 24))分别显著降低了22.6%(P < 0.005)和13%(P < 0.05),尽管CGP74588的AUC((0 - ∞))仅降低了5%(P = 0.28)。酮康唑与伊马替尼联合给药使健康志愿者体内伊马替尼的暴露量增加了40%。鉴于其先前已证实的安全性,这种伊马替尼暴露量的增加可能仅在高剂量时才具有临床意义。在将CYP3A家族抑制剂与伊马替尼联合使用时应考虑这种相互作用。

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