Clinical Pharmacology Program, CCR, National Cancer Institute, NIH, 9000 Rockville Pike, Building 10, Room 5A01, Bethesda, MD, 20892, USA.
Innocrin Pharmaceuticals, Durham, NC, 27703, USA.
Cancer Chemother Pharmacol. 2019 Oct;84(4):759-770. doi: 10.1007/s00280-019-03908-0. Epub 2019 Jul 31.
Seviteronel is an orally-administered selective cytochrome P450c17a 17,20-lyase and androgen receptor inhibitor with anti-tumor activity in vitro and in vivo, and clinical activity in men with advanced castration-resistant prostate cancer (CRPC) and men and women with advanced breast cancer. The purpose of this study was to assess the pharmacokinetics (PK) of seviteronel across the aforementioned populations.
This report describes the PK of seviteronel (50-750 mg, QD or BID) using noncompartmental and population approaches from 243 patients with advanced breast or prostate cancer pooled across 4 clinical studies. First dose and steady-state PK were examined, as well as covariates including prandial status, sex and concomitant dexamethasone.
Seviteronel PK can be characterized by transit absorption and a bi-phasic first-order elimination while accounting for covariance between random effects. Prandial status did not significantly affect any parameters to a clinically-relevant extent. Both sex and body weight were significant covariates on clearance, explaining 37% of the interindividual variability on that parameter. There were no significant effects from the race or the presence of a corticosteroid (either dexamethasone or prednisone).
Seviteronel demonstrates linear PK over the dose range of 50-750 mg given either BID or QD in men with advanced CRPC or men and women with breast cancer. The disposition of seviteronel following oral administration is well described by this population PK model and can be used for accurate simulations for future studies with body weight and sex affecting clearance, but not to a clinically-meaningful degree requiring a change in the current dosing scheme.
塞维特罗尔是一种口服选择性细胞色素 P450c17a17、20-裂合酶和雄激素受体抑制剂，具有体外和体内抗肿瘤活性，以及在晚期去势抵抗性前列腺癌（CRPC）男性和晚期男性和女性乳腺癌患者中的临床活性。本研究的目的是评估 seviteronel 在上述人群中的药代动力学（PK）。
本报告描述了 243 例晚期乳腺癌或前列腺癌患者在 4 项临床研究中的 seviteronel（50-750mg，QD 或 BID）的 PK，采用非房室和群体方法。检查了首剂量和稳态 PK，以及包括进食状态、性别和同时使用地塞米松在内的协变量。
seviteronel PK 可以通过转运吸收和双相一阶消除来描述，同时考虑到随机效应之间的协方差。进食状态对任何参数的影响都没有达到临床相关的显著程度。性别和体重均为清除率的重要协变量，解释了该参数个体间变异性的 37%。种族或皮质类固醇（地塞米松或泼尼松）的存在没有显著影响。
seviteronel 在晚期 CRPC 男性和男性和女性乳腺癌患者中以 BID 或 QD 给予 50-750mg 的剂量范围内表现出线性 PK。该群体 PK 模型很好地描述了 seviteronel 口服给药后的处置情况，可用于未来研究的准确模拟，体重和性别影响清除率，但没有达到需要改变当前剂量方案的临床意义程度。
