Skip to main content
Top
Published in: Cancer Chemotherapy and Pharmacology 4/2019

01-10-2019 | Prostate Cancer | Original Article

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

Authors: Cody J. Peer, Keith T. Schmidt, Jessica D. Kindrick, Joel R. Eisner, Victoria V. Brown, Edwina Baskin-Bey, Ravi Madan, William D. Figg

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2019

Login to get access

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.
Appendix
Available only for authorised users
Literature
2.
go back to reference Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA, Investigators TAX (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351(15):1502–1512. https://doi.org/10.1056/NEJMoa040720 CrossRefPubMed Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA, Investigators TAX (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351(15):1502–1512. https://​doi.​org/​10.​1056/​NEJMoa040720 CrossRefPubMed
3.
go back to reference de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO, Investigators T (2010) Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376(9747):1147–1154. https://doi.org/10.1016/S0140-6736(10)61389-X CrossRefPubMed de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO, Investigators T (2010) Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376(9747):1147–1154. https://​doi.​org/​10.​1016/​S0140-6736(10)61389-X CrossRefPubMed
5.
6.
go back to reference Lea OA, Kvinnsland S, Thorsen T (1989) Improved measurement of androgen receptors in human breast cancer. Can Res 49(24 Pt 1):7162–7167 Lea OA, Kvinnsland S, Thorsen T (1989) Improved measurement of androgen receptors in human breast cancer. Can Res 49(24 Pt 1):7162–7167
7.
go back to reference Soreide JA, Lea OA, Varhaug JE, Skarstein A, Kvinnsland S (1992) Androgen receptors in operable breast cancer: relation to other steroid hormone receptors, correlations to prognostic factors and predictive value for effect of adjuvant tamoxifen treatment. Eur J Surg Oncol 18(2):112–118PubMed Soreide JA, Lea OA, Varhaug JE, Skarstein A, Kvinnsland S (1992) Androgen receptors in operable breast cancer: relation to other steroid hormone receptors, correlations to prognostic factors and predictive value for effect of adjuvant tamoxifen treatment. Eur J Surg Oncol 18(2):112–118PubMed
9.
go back to reference Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B, Investigators P (2014) Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 371(5):424–433. https://doi.org/10.1056/NEJMoa1405095 CrossRefPubMedPubMedCentral Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B, Investigators P (2014) Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 371(5):424–433. https://​doi.​org/​10.​1056/​NEJMoa1405095 CrossRefPubMedPubMedCentral
10.
go back to reference Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Flechon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS, Investigators A (2012) Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367(13):1187–1197. https://doi.org/10.1056/NEJMoa1207506 CrossRefPubMed Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Flechon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS, Investigators A (2012) Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367(13):1187–1197. https://​doi.​org/​10.​1056/​NEJMoa1207506 CrossRefPubMed
11.
go back to reference de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Flechon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI, Investigators C-A (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364(21):1995–2005. https://doi.org/10.1056/NEJMoa1014618 CrossRefPubMedPubMedCentral de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Flechon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI, Investigators C-A (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364(21):1995–2005. https://​doi.​org/​10.​1056/​NEJMoa1014618 CrossRefPubMedPubMedCentral
12.
go back to reference Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, Carles J, Flaig TW, Taplin ME, Higano CS, de Souza P, de Bono JS, Griffin TW, De Porre P, Yu MK, Park YC, Li J, Kheoh T, Naini V, Molina A, Rathkopf DE, Investigators C-A (2015) Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 16(2):152–160. https://doi.org/10.1016/S1470-2045(14)71205-7 CrossRefPubMed Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, Carles J, Flaig TW, Taplin ME, Higano CS, de Souza P, de Bono JS, Griffin TW, De Porre P, Yu MK, Park YC, Li J, Kheoh T, Naini V, Molina A, Rathkopf DE, Investigators C-A (2015) Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 16(2):152–160. https://​doi.​org/​10.​1016/​S1470-2045(14)71205-7 CrossRefPubMed
14.
go back to reference Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O’Shaughnessy J, Gradishar W, Schmid P, Winer E, Kelly C, Nanda R, Gucalp A, Awada A, Garcia-Estevez L, Trudeau ME, Steinberg J, Uppal H, Tudor IC, Peterson A, Cortes J (2018) Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol 36(9):884–890. https://doi.org/10.1200/JCO.2016.71.3495 CrossRefPubMedPubMedCentral Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O’Shaughnessy J, Gradishar W, Schmid P, Winer E, Kelly C, Nanda R, Gucalp A, Awada A, Garcia-Estevez L, Trudeau ME, Steinberg J, Uppal H, Tudor IC, Peterson A, Cortes J (2018) Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol 36(9):884–890. https://​doi.​org/​10.​1200/​JCO.​2016.​71.​3495 CrossRefPubMedPubMedCentral
15.
go back to reference Bonnefoi H, Grellety T, Tredan O, Saghatchian M, Dalenc F, Mailliez A, L’Haridon T, Cottu P, Abadie-Lacourtoisie S, You B, Mousseau M, Dauba J, Del Piano F, Desmoulins I, Coussy F, Madranges N, Grenier J, Bidard FC, Proudhon C, MacGrogan G, Orsini C, Pulido M, Goncalves A (2016) A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1). Ann Oncol 27(5):812–818. https://doi.org/10.1093/annonc/mdw067 CrossRefPubMed Bonnefoi H, Grellety T, Tredan O, Saghatchian M, Dalenc F, Mailliez A, L’Haridon T, Cottu P, Abadie-Lacourtoisie S, You B, Mousseau M, Dauba J, Del Piano F, Desmoulins I, Coussy F, Madranges N, Grenier J, Bidard FC, Proudhon C, MacGrogan G, Orsini C, Pulido M, Goncalves A (2016) A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1). Ann Oncol 27(5):812–818. https://​doi.​org/​10.​1093/​annonc/​mdw067 CrossRefPubMed
20.
go back to reference Norris JD, Ellison SJ, Baker JG, Stagg DB, Wardell SE, Park S, Alley HM, Baldi RM, Yllanes A, Andreano KJ, Stice JP, Lawrence SA, Eisner JR, Price DK, Moore WR, Figg WD, McDonnell DP (2017) Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer. J Clin Invest 127(6):2326–2338. https://doi.org/10.1172/JCI87328 CrossRefPubMedPubMedCentral Norris JD, Ellison SJ, Baker JG, Stagg DB, Wardell SE, Park S, Alley HM, Baldi RM, Yllanes A, Andreano KJ, Stice JP, Lawrence SA, Eisner JR, Price DK, Moore WR, Figg WD, McDonnell DP (2017) Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer. J Clin Invest 127(6):2326–2338. https://​doi.​org/​10.​1172/​JCI87328 CrossRefPubMedPubMedCentral
22.
go back to reference Bardia A, Gucalp A, DaCosta N, Gabrail N, Danso M, Ali H, Blackwell KL, Carey LA, Eisner JR, Baskin-Bey ES, Traina TA (2018) Phase 1 study of seviteronel, a selective CYP17 lyase and androgen receptor inhibitor, in women with estrogen receptor-positive or triple-negative breast cancer. Breast Cancer Res Treat 171(1):9. https://doi.org/10.1007/s10549-018-4813-z CrossRef Bardia A, Gucalp A, DaCosta N, Gabrail N, Danso M, Ali H, Blackwell KL, Carey LA, Eisner JR, Baskin-Bey ES, Traina TA (2018) Phase 1 study of seviteronel, a selective CYP17 lyase and androgen receptor inhibitor, in women with estrogen receptor-positive or triple-negative breast cancer. Breast Cancer Res Treat 171(1):9. https://​doi.​org/​10.​1007/​s10549-018-4813-z CrossRef
24.
go back to reference Attard G, Reid AH, Auchus RJ, Hughes BA, Cassidy AM, Thompson E, Oommen NB, Folkerd E, Dowsett M, Arlt W, de Bono JS (2012) Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer. J Clin Endocrinol Metab 97(2):507–516. https://doi.org/10.1210/jc.2011-2189 CrossRefPubMed Attard G, Reid AH, Auchus RJ, Hughes BA, Cassidy AM, Thompson E, Oommen NB, Folkerd E, Dowsett M, Arlt W, de Bono JS (2012) Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer. J Clin Endocrinol Metab 97(2):507–516. https://​doi.​org/​10.​1210/​jc.​2011-2189 CrossRefPubMed
28.
Metadata
Title
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
Authors
Cody J. Peer
Keith T. Schmidt
Jessica D. Kindrick
Joel R. Eisner
Victoria V. Brown
Edwina Baskin-Bey
Ravi Madan
William D. Figg
Publication date
01-10-2019
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 4/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-019-03908-0

Other articles of this Issue 4/2019

Cancer Chemotherapy and Pharmacology 4/2019 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine