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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.
- Authors
Xu, Xu; Ryan, Charles; Stuyckens, Kim; Smith, Matthew; Saad, Fred; Griffin, Thomas; Park, Youn; Yu, Margaret; Porre, Peter; Vermeulen, An; Poggesi, Italo; Nandy, Partha; Xu, Xu Steven; Ryan, Charles J; Smith, Matthew R; Griffin, Thomas W; Park, Youn C; Yu, Margaret K; De Porre, Peter
- Abstract
<bold>Background and Objectives: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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.
- Subjects
PROSTATE-specific antigen; DRUG resistance in cancer cells; CASTRATION; STEROID drugs; PROSTATE cancer treatment; BIOLOGICAL models; COMBINATION drug therapy; CLINICAL trials; COMPARATIVE studies; LACTATE dehydrogenase; RESEARCH methodology; MEDICAL cooperation; PHARMACOKINETICS; PREDNISONE; PROSTATE tumors; RESEARCH; TESTOSTERONE; SOCIOECONOMIC factors; EVALUATION research; PHARMACODYNAMICS
- Publication
Clinical Pharmacokinetics, 2017, Vol 56, Issue 1, p55
- ISSN
0312-5963
- Publication type
journal article
- DOI
10.1007/s40262-016-0425-0