Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer

Xu Steven Xu; Charles J. Ryan; Kim Stuyckens; Matthew R. Smith; Fred Saad; Thomas W. Griffin; Youn C. Park; Margaret K. Yu; Peter De Porre; An Vermeulen; Italo Poggesi; Partha Nandy

doi:10.1007/s40262-016-0425-0

Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer

Xu Steven Xu, Charles J. Ryan, Kim Stuyckens, Matthew R. Smith, Fred Saad, Thomas W. Griffin, Youn C. Park, Margaret K. Yu, Peter De Porre, An Vermeulen, Italo Poggesi, Partha Nandy

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Abstract

Background and Objectives: Recent analysis revealed strong associations between prostate-specific antigen (PSA) dynamics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) and supported PSA dynamics as bridging surrogacy endpoints for clinical benefit from treatment with abiraterone acetate plus prednisone. This analysis aimed to investigate the abiraterone exposure–PSA dynamics relationship in mCRPC. Methods: Abiraterone pharmacokinetics–PSA models were constructed using data from the COU-AA-301 (chemotherapy-pretreated) and COU-AA-302 (chemotherapy-naïve) trials comparing abiraterone acetate 1000 mg/day plus prednisone 5 mg twice daily with prednisone alone in mCRPC. The drug effect–PSA dynamics relationship was modeled as a function of selected pharmacokinetic measures. The influences of baseline demographic variables, laboratory values, and disease status on PSA dynamics were assessed. Results: A tumor growth inhibition model best described PSA dynamics post-treatment with abiraterone acetate. Abiraterone acetate treatment in chemotherapy-pretreated and chemotherapy-naïve patients increased the PSA decay rate (k_dec) to the same extent (1.28-fold, 95 % confidence interval [CI] 0.58–1.98; and 0.93-fold, 95 % CI 0.6–1.27, respectively). Lower baseline lactate dehydrogenase and higher baseline testosterone significantly increased k_dec. Findings from our analysis suggest a maximum-effect relationship between abiraterone trough concentration and PSA dynamics in both patient populations. The majority of patients had a steady-state trough concentration greater than the estimated half maximal effective concentration. Conclusion: The model appropriately described the exposure–response relationship between abiraterone and PSA dynamics in chemotherapy-pretreated and chemotherapy-naïve patients following oral administration of abiraterone acetate.

Original language	English (US)
Pages (from-to)	55-63
Number of pages	9
Journal	Clinical Pharmacokinetics
Volume	56
Issue number	1
DOIs	https://doi.org/10.1007/s40262-016-0425-0
State	Published - Jan 1 2017
Externally published	Yes

Bibliographical note

Funding Information:
This study was sponsored by Janssen Research & Development, Raritan, NJ, USA. Writing assistance was provided by S. Thomas, PhD, of PAREXEL, and was funded by Janssen Global Services, LLC.

Publisher Copyright:
© 2016, Springer International Publishing Switzerland.

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Xu, X. S., Ryan, C. J., Stuyckens, K., Smith, M. R., Saad, F., Griffin, T. W., Park, Y. C., Yu, M. K., De Porre, P., Vermeulen, A., Poggesi, I., & Nandy, P. (2017). Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer. Clinical Pharmacokinetics, 56(1), 55-63. https://doi.org/10.1007/s40262-016-0425-0

Xu, XS, Ryan, CJ, Stuyckens, K, Smith, MR, Saad, F, Griffin, TW, Park, YC, Yu, MK, De Porre, P, Vermeulen, A, Poggesi, I & Nandy, P 2017, 'Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer', Clinical Pharmacokinetics, vol. 56, no. 1, pp. 55-63. https://doi.org/10.1007/s40262-016-0425-0

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title = "Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer",

abstract = "Background and Objectives: Recent analysis revealed strong associations between prostate-specific antigen (PSA) dynamics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) and supported PSA dynamics as bridging surrogacy endpoints for clinical benefit from treatment with abiraterone acetate plus prednisone. This analysis aimed to investigate the abiraterone exposure–PSA dynamics relationship in mCRPC. Methods: Abiraterone pharmacokinetics–PSA models were constructed using data from the COU-AA-301 (chemotherapy-pretreated) and COU-AA-302 (chemotherapy-na{\"i}ve) trials comparing abiraterone acetate 1000 mg/day plus prednisone 5 mg twice daily with prednisone alone in mCRPC. The drug effect–PSA dynamics relationship was modeled as a function of selected pharmacokinetic measures. The influences of baseline demographic variables, laboratory values, and disease status on PSA dynamics were assessed. Results: A tumor growth inhibition model best described PSA dynamics post-treatment with abiraterone acetate. Abiraterone acetate treatment in chemotherapy-pretreated and chemotherapy-na{\"i}ve patients increased the PSA decay rate (kdec) to the same extent (1.28-fold, 95 % confidence interval [CI] 0.58–1.98; and 0.93-fold, 95 % CI 0.6–1.27, respectively). Lower baseline lactate dehydrogenase and higher baseline testosterone significantly increased kdec. Findings from our analysis suggest a maximum-effect relationship between abiraterone trough concentration and PSA dynamics in both patient populations. The majority of patients had a steady-state trough concentration greater than the estimated half maximal effective concentration. Conclusion: The model appropriately described the exposure–response relationship between abiraterone and PSA dynamics in chemotherapy-pretreated and chemotherapy-na{\"i}ve patients following oral administration of abiraterone acetate.",

author = "Xu, {Xu Steven} and Ryan, {Charles J.} and Kim Stuyckens and Smith, {Matthew R.} and Fred Saad and Griffin, {Thomas W.} and Park, {Youn C.} and Yu, {Margaret K.} and {De Porre}, Peter and An Vermeulen and Italo Poggesi and Partha Nandy",

note = "Funding Information: This study was sponsored by Janssen Research & Development, Raritan, NJ, USA. Writing assistance was provided by S. Thomas, PhD, of PAREXEL, and was funded by Janssen Global Services, LLC. Publisher Copyright: {\textcopyright} 2016, Springer International Publishing Switzerland.",

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doi = "10.1007/s40262-016-0425-0",

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T1 - Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer

AU - Xu, Xu Steven

AU - Ryan, Charles J.

AU - Stuyckens, Kim

AU - Smith, Matthew R.

AU - Saad, Fred

AU - Griffin, Thomas W.

AU - Park, Youn C.

AU - Yu, Margaret K.

AU - De Porre, Peter

AU - Vermeulen, An

AU - Poggesi, Italo

AU - Nandy, Partha

N1 - Funding Information: This study was sponsored by Janssen Research & Development, Raritan, NJ, USA. Writing assistance was provided by S. Thomas, PhD, of PAREXEL, and was funded by Janssen Global Services, LLC. Publisher Copyright: © 2016, Springer International Publishing Switzerland.

PY - 2017/1/1

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N2 - Background and Objectives: Recent analysis revealed strong associations between prostate-specific antigen (PSA) dynamics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) and supported PSA dynamics as bridging surrogacy endpoints for clinical benefit from treatment with abiraterone acetate plus prednisone. This analysis aimed to investigate the abiraterone exposure–PSA dynamics relationship in mCRPC. Methods: Abiraterone pharmacokinetics–PSA models were constructed using data from the COU-AA-301 (chemotherapy-pretreated) and COU-AA-302 (chemotherapy-naïve) trials comparing abiraterone acetate 1000 mg/day plus prednisone 5 mg twice daily with prednisone alone in mCRPC. The drug effect–PSA dynamics relationship was modeled as a function of selected pharmacokinetic measures. The influences of baseline demographic variables, laboratory values, and disease status on PSA dynamics were assessed. Results: A tumor growth inhibition model best described PSA dynamics post-treatment with abiraterone acetate. Abiraterone acetate treatment in chemotherapy-pretreated and chemotherapy-naïve patients increased the PSA decay rate (kdec) to the same extent (1.28-fold, 95 % confidence interval [CI] 0.58–1.98; and 0.93-fold, 95 % CI 0.6–1.27, respectively). Lower baseline lactate dehydrogenase and higher baseline testosterone significantly increased kdec. Findings from our analysis suggest a maximum-effect relationship between abiraterone trough concentration and PSA dynamics in both patient populations. The majority of patients had a steady-state trough concentration greater than the estimated half maximal effective concentration. Conclusion: The model appropriately described the exposure–response relationship between abiraterone and PSA dynamics in chemotherapy-pretreated and chemotherapy-naïve patients following oral administration of abiraterone acetate.

AB - Background and Objectives: Recent analysis revealed strong associations between prostate-specific antigen (PSA) dynamics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) and supported PSA dynamics as bridging surrogacy endpoints for clinical benefit from treatment with abiraterone acetate plus prednisone. This analysis aimed to investigate the abiraterone exposure–PSA dynamics relationship in mCRPC. Methods: Abiraterone pharmacokinetics–PSA models were constructed using data from the COU-AA-301 (chemotherapy-pretreated) and COU-AA-302 (chemotherapy-naïve) trials comparing abiraterone acetate 1000 mg/day plus prednisone 5 mg twice daily with prednisone alone in mCRPC. The drug effect–PSA dynamics relationship was modeled as a function of selected pharmacokinetic measures. The influences of baseline demographic variables, laboratory values, and disease status on PSA dynamics were assessed. Results: A tumor growth inhibition model best described PSA dynamics post-treatment with abiraterone acetate. Abiraterone acetate treatment in chemotherapy-pretreated and chemotherapy-naïve patients increased the PSA decay rate (kdec) to the same extent (1.28-fold, 95 % confidence interval [CI] 0.58–1.98; and 0.93-fold, 95 % CI 0.6–1.27, respectively). Lower baseline lactate dehydrogenase and higher baseline testosterone significantly increased kdec. Findings from our analysis suggest a maximum-effect relationship between abiraterone trough concentration and PSA dynamics in both patient populations. The majority of patients had a steady-state trough concentration greater than the estimated half maximal effective concentration. Conclusion: The model appropriately described the exposure–response relationship between abiraterone and PSA dynamics in chemotherapy-pretreated and chemotherapy-naïve patients following oral administration of abiraterone acetate.

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Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer

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