Pharmacokinetics of Lorlatinib After Single and Multiple Dosing in Patients with Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer: Results from a Global Phase I/II Study.
Pharmacokinetics of Lorlatinib After Single and Multiple Dosing in Patients with Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer: Results from a Global Phase I/II Study.
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DOI：
10.1007/s40262-021-01015-z
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发表时间：
2021-10
影响因子：
4.5
通讯作者：
Pithavala YK
中科院分区：
文献类型：
--
作者：
Chen J;O'Gorman MT;James LP;Klamerus KJ;Mugundu G;Pithavala YK
洛拉替尼在一项I/II期研究(NCT01970865)中证明了对间变性淋巴瘤激酶(ALK)阳性非小细胞肺癌(NSCLC)患者的疗效(包括颅内活动)。这项分析描述了单次和多次给药后劳拉替尼的药代动力学(PK)。这项正在进行的多中心、开放标签、单臂I/II期试验纳入了ALK阳性或c-ros癌基因1(ROS1)阳性的晚期非小细胞肺癌患者。在第一阶段，患者在连续21天的周期中接受递增剂量的劳拉替尼(10-200毫克，每天一次)和每天两次，35，75和100毫克的剂量。在第二阶段，劳拉替尼的起始量为100毫克，每天一次，连续21天为一个周期。研究的参数包括劳拉替尼抑制/诱导细胞色素P450(CYP)3A的潜力；劳拉替尼及其主要代谢物PF-06895751的吸收/代谢；以及亚洲和非亚洲患者之间这些参数的差异。第一阶段的54名患者和第二阶段的275名患者获得了数据。洛拉替尼的血浆暴露在单次剂量10-200 mg后按剂量比例增加，在多次剂量后略低于按剂量比例增加。与单次给药相比，多次给药后洛拉替尼清除量增加，这表明是自动诱导。多次给药后，PF-06895751的药时曲线下面积较劳拉替尼大约80%。洛拉替尼显示出脑穿透能力。此外，亚裔和非亚裔患者之间的单剂和多剂PK参数没有明显差异。洛拉替尼具有高度的脑渗透性，在多次给药后表现出自动诱导作用。在健康受试者和癌症患者之间，或者在亚洲人和非亚洲人之间，劳拉替尼的PK似乎没有固有的差异。临床试验.gov NCT01970865。网上版载有补充材料，可在10.1007/s40262-021-01015-z查阅。
Lorlatinib demonstrated efficacy (including intracranial activity) in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in a phase I/II study (NCT01970865). This analysis describes the pharmacokinetics (PK) of lorlatinib following single and multiple dosing. This ongoing, multicenter, open-label, single-arm, phase I/II trial enrolled patients with ALK-positive or c-ros oncogene 1 (ROS1)-positive advanced NSCLC. In phase I, patients received escalating doses of lorlatinib (10–200 mg orally once daily) and twice-daily doses of 35, 75, and 100 mg in continuous 21-day cycles. In phase II, lorlatinib was administered at a starting dose of 100 mg once daily in continuous 21-day cycles. Parameters investigated included the potential for lorlatinib to inhibit/induce cytochrome P450 (CYP) 3A; the absorption/metabolism of lorlatinib and its major metabolite PF-06895751; and differences in these parameters between Asian and non-Asian patients. Data were available for 54 patients from phase I and 275 patients from phase II. Lorlatinib plasma exposure increased dose proportionally after single doses of 10–200 mg, and slightly less than dose proportionally after multiple doses. Lorlatinib clearance increased following multiple dosing compared with single dosing, indicating autoinduction. The area under the concentration-time curve from time zero to time τ (the dosing interval; AUCτ) of PF-06895751 was approximately 80% higher than that of lorlatinib after multiple dosing. Lorlatinib exhibited brain penetration. Furthermore, no overt differences in single- and multiple-dose PK parameters between the Asian and non-Asian patients were observed. Lorlatinib is highly brain penetrant and exhibits autoinduction after multiple dosing. There appears to be no inherent differences in lorlatinib PK between healthy subjects and cancer patients, or between Asian and non-Asian patients. ClinicalTrials.gov NCT01970865. The online version contains supplementary material available at 10.1007/s40262-021-01015-z.
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影响因子：
11.5
作者：
Syed, Yahiya Y.
通讯作者：
Syed, Yahiya Y.
影响因子：
2.9
作者：
Stypinski, Daria;Fostvedt, Luke;Pithavala, Yazdi K.
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