伦伐替尼(LEN),用于各种癌症治疗的多靶点酪氨酸激酶抑制剂,主要由细胞色素P4503A(CYP3A)酶代谢。已经提出了在施用LEN的患者中治疗药物监测(TDM)的重要性。尽管已经报道了一些内源性CYP3A活性的生物标志物,它们在剂量调整中的效用尚未得到很好的评估。这项研究调查了临床实践中血浆LEN浓度与内源性尿CYP3A生物标志物之间的相关性。血浆LEN(N=225)和CYP3A生物标志物(皮质醇,6β-羟基皮质醇,脱氧胆酸,20例患者(肝细胞癌,N=6;甲状腺癌,N=3;子宫内膜癌,N=8;和肾细胞癌,使用液相色谱-串联质谱法评估收集的长达1年的咨询N=3)。此外,对于在样品收集前给予LEN的门诊患者,使用具有线性消除的三室模型预测血浆谷LEN浓度.在定量的实际浓度和预测的LEN谷浓度之间观察到中等相关性,而与内源性尿CYP3A生物标志物无相关性。无法确定内源性尿CYP3A生物标志物的效用。然而,可以使用非线性混合效应模型(NONMEM)预测门诊患者口服可用药物的TDM。这项研究调查了内源性尿CYP3A生物标志物用于个性化医疗和NONMEM用于预测血浆药物浓度的实用性。这些发现将为进一步的临床研究和详细的TDM提供重要信息。
Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6β-hydroxycortisol, deoxycholic acid, and 1β-hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography-tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three-compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM.