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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

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Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusions

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.

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Acknowledgements

The authors would like to thank all the patients, nurses, and other medical personnel who participated in these trials, as well as Karin Jorga who assisted in the data analysis and interpretation of the noncompartmental PK results.

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Authors and Affiliations

  1. Clinical Pharmacology Program, CCR, National Cancer Institute, NIH, 9000 Rockville Pike, Building 10, Room 5A01, Bethesda, MD, 20892, USA

    Cody J. Peer, Keith T. Schmidt, Jessica D. Kindrick & William D. Figg

  2. Innocrin Pharmaceuticals, Durham, NC, 27703, USA

    Joel R. Eisner, Victoria V. Brown & Edwina Baskin-Bey

  3. Genitourinary Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD, 20892, USA

    Ravi Madan

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  1. Cody J. Peer
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Correspondence to William D. Figg.

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Conflict of interest

JRE is an employee and shareholder and VVB is an employee of Innocrin Pharmaceuticals. All other authors declared no conflicts of interest and have nothing to disclose.

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This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, Grant ZIC SC 006537.

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Peer, C.J., Schmidt, K.T., Kindrick, J.D. et al. 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. Cancer Chemother Pharmacol 84, 759–770 (2019). https://doi.org/10.1007/s00280-019-03908-0

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