A population pharmacokinetic analysis of the oral CYP17 lyase and androgen receptor inhibitor seviteronel in patients with advanced/metastatic castration-resistant prostate cancer or breast cancer

• DOI: 10.1007/s00280-019-03908-0
• Publication Date: 2019-07-31T17:02:52Z
• Authors: Cody J. Peer; Keith T. Schmidt; Jessica D. Kindrick; Joel R. Eisner; Victoria V. Brown; Edwina Baskin-Bey; Ravi Madan; William D. Figg
• Keywords: Male; Dose-Response Relationship, Drug; Biological Availability; Steroid 17-alpha-Hydroxylase; Antineoplastic Agents; Breast Neoplasms; Naphthalenes; Triazoles; Dexamethasone; 3. Good health; Prostatic Neoplasms, Castration-Resistant; 03 medical and health sciences; Clinical Trials, Phase II as Topic; 0302 clinical medicine; Androgen Receptor Antagonists; Humans; Drug Therapy, Combination; Female; Drug Monitoring; Neoplasm Staging

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.