Dutreix Catherine, Lorenzo Sebastien, Wang Yanfeng
Novartis Pharma AG Basel, Basel, Switzerland.
Eur J Clin Pharmacol. 2014 Aug;70(8):915-20. doi: 10.1007/s00228-014-1675-0. Epub 2014 May 21.
Midostaurin, a multitargeted tyrosine kinase inhibitor, is primarily metabolized by CYP3A4. This midostaurin drug-drug interaction study assessed the dynamic response and clinical usefulness of urinary 6β-hydroxycortisol to cortisol ratio (6βCR) and plasma 4β-hydroxycholesterol (4βHC) for monitoring CYP3A4 activity in the presence or absence of rifampicin, a strong CYP3A4 inducer.
Forty healthy adults were randomized into groups for either placebo or treatment with rifampicin 600 mg QD for 14 days. All participants received midostaurin 50 mg on day 9. Midostaurin plasma pharmacokinetic parameters were assessed. Urinary 6βCR and plasma 4βHC levels were measured on days 1, 9, 11, and 15.
Both markers remained stable over time in the control group and increased significantly in the rifampicin group. In the rifampicin group, the median increases (vs day 1) on days 9, 11, and 15 were 4.1-, 5.2-, and 4.7-fold, respectively, for 6βCR and 3.4-, 4.1-, and 4.7-fold, respectively, for 4βHC. Inter- and intrasubject variabilities in the control group were 45.6 % and 30.5 %, respectively, for 6βCR, and 33.8 % and 7.5 %, respectively, for 4βHC. Baseline midostaurin area under the concentration-time curve (AUC) correlated with 4βHC levels (ρ = -0.72; P = .003), but not with 6βCR (ρ = 0.0925; P = .6981).
Both 6βCR and 4βHC levels showed a good dynamic response range upon strong CYP3A4 induction with rifampicin. Because of lower inter- and intrasubject variability, 4βHC appeared more reliable and better predictive of CYP3A4 activity compared with 6βCR. The data from our study further support the clinical utility of these biomarkers.
米哚妥林是一种多靶点酪氨酸激酶抑制剂，主要通过CYP3A4代谢。这项米哚妥林药物相互作用研究评估了在有或没有利福平（一种强效CYP3A4诱导剂）存在的情况下，尿6β-羟基皮质醇与皮质醇比值（6βCR）和血浆4β-羟基胆固醇（4βHC）监测CYP3A4活性的动态反应及临床实用性。
40名健康成年人被随机分为安慰剂组或接受利福平600mg每日一次治疗14天的治疗组。所有参与者在第9天接受米哚妥林50mg。评估米哚妥林的血浆药代动力学参数。在第1、9、11和15天测量尿6βCR和血浆4βHC水平。
在对照组中，两种标志物随时间保持稳定，而在利福平组中显著升高。在利福平组中，第9、11和15天相对于第1天的中位数升高，6βCR分别为4.1倍、5.2倍和4.7倍，4βHC分别为3.4倍、4.1倍和4.7倍。对照组中，6βCR的受试者间和受试者内变异性分别为45.6%和30.5%，4βHC分别为33.8%和7.5%。基线米哚妥林浓度-时间曲线下面积（AUC）与4βHC水平相关（ρ = -0.72；P = 0.003），但与6βCR不相关（ρ = 0.0925；P = 0.6981）。
在利福平强效诱导CYP3A4时，6βCR和4βHC水平均显示出良好的动态反应范围。由于受试者间和受试者内变异性较低，与6βCR相比，4βHC似乎更可靠，对CYP3A4活性的预测性更好。我们研究的数据进一步支持了这些生物标志物的临床实用性。
