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咪达唑仑作为一种表型探针,用于预测癌症患者接受舒尼替尼治疗时的暴露情况。

Midazolam as a phenotyping probe to predict sunitinib exposure in patients with cancer.

机构信息

Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.

出版信息

Cancer Chemother Pharmacol. 2014 Jan;73(1):87-96. doi: 10.1007/s00280-013-2322-7. Epub 2013 Oct 23.

Abstract

PURPOSE

Patients treated with sunitinib show substantial inter-patient variability in drug exposure (~30-40 %), which is largely unexplained. Since sunitinib is metabolized by cytochrome P450(CYP)3A4, variability in the activity of this enzyme may explain a considerable proportion of this inter-patient variability. Midazolam is widely used as a phenotyping probe to assess CYP3A4-activity. The objective of this study was to prospectively evaluate the relationship between midazolam and sunitinib exposure. Additionally, the correlation between sunitinib trough levels and exposure and the influence of sunitinib on midazolam exposure was determined.

METHODS

Thirteen patients treated with sunitinib in a 4 weeks "on"-2 weeks "off" regimen received twice 7.5 mg midazolam; once with and once without sunitinib. Steady-state sunitinib, its active metabolite SU12662 and midazolam exposures were determined.

RESULTS

A significant correlation between midazolam exposure (AUC(0-7h)) and steady-state sunitinib and sunitinib + SU12662 exposure (AUC(0-24h)) was found (p = 0.006 and p = 0.0018, respectively); midazolam exposure explained 51 and 41 % of the inter-patient variability in sunitinib and sunitinib + SU12622 exposure. Furthermore, C trough was highly correlated (r(2) = 0.94) with sunitinib AUC(0-24h). Sunitinib decreased midazolam exposure with 24 % (p = 0.034).

CONCLUSION

Midazolam exposure is highly correlated with sunitinib exposure and explains a large proportion of the observed inter-patient variability in sunitinib pharmacokinetics. Consequently, midazolam could be used to identify patients that are at risk of under- or overtreatment, respectively, at the start of sunitinib therapy. Moreover, sunitinib and sunitinib + SU12662 trough levels are highly correlated with drug exposure and can thus be used in clinical practice to individualize sunitinib therapy. The decrease in midazolam exposure by sunitinib needs further investigation.

摘要

目的

接受舒尼替尼治疗的患者在药物暴露方面存在显著的个体间变异性(~30-40%),而这种变异性在很大程度上尚未得到解释。由于舒尼替尼主要通过细胞色素 P450(CYP)3A4 代谢,因此这种酶的活性变化可能解释了这种个体间变异性的相当大一部分。咪达唑仑被广泛用作评估 CYP3A4 活性的表型探针。本研究的目的是前瞻性评估咪达唑仑与舒尼替尼暴露之间的关系。此外,还确定了舒尼替尼谷浓度与暴露之间的相关性以及舒尼替尼对咪达唑仑暴露的影响。

方法

13 名接受舒尼替尼 4 周“给药”和 2 周“停药”方案治疗的患者,分别接受两次 7.5 mg 咪达唑仑;一次给药,一次不给药。测定稳态舒尼替尼及其活性代谢物 SU12662 和咪达唑仑的暴露量。

结果

咪达唑仑暴露量(AUC(0-7h))与稳态舒尼替尼和舒尼替尼+SU12662 暴露量(AUC(0-24h))呈显著相关性(p=0.006 和 p=0.0018,分别);咪达唑仑暴露量解释了舒尼替尼和舒尼替尼+SU12622 暴露量个体间变异性的 51%和 41%。此外,C 谷浓度与舒尼替尼 AUC(0-24h)高度相关(r(2)=0.94)。舒尼替尼使咪达唑仑暴露量降低了 24%(p=0.034)。

结论

咪达唑仑暴露量与舒尼替尼暴露量高度相关,解释了舒尼替尼药代动力学观察到的个体间变异性的很大一部分。因此,咪达唑仑可用于在舒尼替尼治疗开始时识别处于治疗不足或过度治疗风险的患者。此外,舒尼替尼和舒尼替尼+SU12662 谷浓度与药物暴露量高度相关,因此可在临床实践中用于个体化舒尼替尼治疗。舒尼替尼降低咪达唑仑暴露量的作用还需要进一步研究。

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