Abiraterone

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Matthew R Smith - One of the best experts on this subject based on the ideXlab platform.

  • clinical outcomes from androgen signaling directed therapy after treatment with Abiraterone acetate and prednisone in patients with metastatic castration resistant prostate cancer post hoc analysis of cou aa 302
    European Urology, 2017
    Co-Authors: Matthew R Smith, Karim Fizazi, Thian Kheoh, Dana E Rathkopf, Johann S De Bono, Neal D Shore, Peter F A Mulders, Eric J Small, Fred Saad, Peter De Porre
    Abstract:

    Abstract In the COU-AA-302 trial, Abiraterone acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling–directed therapies following Abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent Abiraterone acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6–not estimable) for subsequent Abiraterone acetate plus prednisone and 2.8 mo (range 1.8–not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent Abiraterone acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with Abiraterone acetate plus prednisone or enzalutamide for patients who progressed on Abiraterone acetate is associated with limited clinical benefit. Patient summary This analysis showed limited clinical benefit for subsequent Abiraterone acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with Abiraterone acetate plus prednisone. This analysis does not support prioritization of subsequent Abiraterone acetate plus prednisone or enzalutamide following initial therapy with Abiraterone acetate plus prednisone.

  • Clinical Outcomes from Androgen Signaling–directed Therapy after Treatment with Abiraterone Acetate and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302
    European urology, 2017
    Co-Authors: Matthew R Smith, Karim Fizazi, Dana E Rathkopf, Johann S De Bono, Neal D Shore, Peter F A Mulders, Eric J Small, Fred Saad, Thian Kheoh
    Abstract:

    Abstract In the COU-AA-302 trial, Abiraterone acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling–directed therapies following Abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent Abiraterone acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6–not estimable) for subsequent Abiraterone acetate plus prednisone and 2.8 mo (range 1.8–not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent Abiraterone acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with Abiraterone acetate plus prednisone or enzalutamide for patients who progressed on Abiraterone acetate is associated with limited clinical benefit. Patient summary This analysis showed limited clinical benefit for subsequent Abiraterone acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with Abiraterone acetate plus prednisone. This analysis does not support prioritization of subsequent Abiraterone acetate plus prednisone or enzalutamide following initial therapy with Abiraterone acetate plus prednisone.

  • Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer
    Clinical Pharmacokinetics, 2017
    Co-Authors: Charles J. Ryan, Matthew R Smith, Fred Saad, Peter De Porre, Thomas W. Griffin, Kim Stuyckens, An Vermeulen, Italo Poggesi, Youn C. Park, Partha Nandy
    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.

  • Efficacy and Safety of Abiraterone Acetate in Elderly (75 Years or Older) Chemotherapy Naïve Patients with Metastatic Castration Resistant Prostate Cancer.
    The Journal of urology, 2015
    Co-Authors: Matthew R Smith, Arturo Molina, Thian Kheoh, Dana E Rathkopf, Peter F A Mulders, Joan Carles, Hendrik Van Poppel, Thomas W. Griffin, Charles J. Ryan
    Abstract:

    Purpose: Metastatic castration resistant prostate cancer primarily affects elderly men. In this post hoc analysis we investigated the safety and efficacy of Abiraterone acetate in elderly (age 75 years or greater) and younger (less than 75 years) patient subgroups at the prespecified interim analysis (55% of total overall survival events) for the COU-AA-302 (Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer) trial.Materials and Methods: Patients were stratified and randomized 1:1 to Abiraterone acetate 1,000 mg plus prednisone/prednisolone 5 mg twice daily (Abiraterone-prednisone) vs placebo plus prednisone/prednisolone 5 mg twice daily (prednisone alone). Co-primary end points were radiographic progression-free and overall survival. Median time to event and HR were estimated using the Kaplan-Meier method and a Cox model, respectively.Results: A total of 350 elderly patients treated with Abiraterone-prednisone had significant improvemen...

  • Population Pharmacokinetic Analysis of Abiraterone in Chemotherapy-Naïve and Docetaxel-Treated Patients with Metastatic Castration-Resistant Prostate Cancer
    Clinical Pharmacokinetics, 2014
    Co-Authors: Kim Stuyckens, Matthew R Smith, Charles J. Ryan, Fred Saad, Thomas W. Griffin, Xu Steven Xu, Margaret K. Yu, An Vermeulen, Partha Nandy, Italo Poggesi
    Abstract:

    Background and Objectives Abiraterone acetate, an androgen biosynthesis inhibitor, prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) in the pre- and post-chemotherapy setting as demonstrated by the pivotal phase III studies COU-AA-301 and COU-AA-302. We performed population pharmacokinetic analyses to estimate pharmacokinetic parameters after oral administration of 1,000 mg/day of Abiraterone acetate in patients with mCRPC, with or without prior chemotherapy, and after a single 1,000 mg dose in healthy volunteers. The study objectives were to determine consistency between patient populations and to characterize factors that may influence Abiraterone pharmacokinetics. Methods Studies in this analysis included COU-AA-302 (chemotherapy naïve); COU-AA-301 and COU-AA-006 (chemotherapy pretreated); and COU-AA-008, COU-AA-009, and COU-AA-014 (healthy subjects). A total of 4,627 plasma concentrations from 359 subjects (62 healthy volunteers, 297 patients) were analyzed using non-linear mixed-effects modeling. Results An Erlang-type absorption model with first-order elimination and three-transit compartments following sequential zero- and first-order processes was used to characterize Abiraterone pharmacokinetics. Absorption-related parameters were affected by food intake. Abiraterone pharmacokinetics were characterized by an extensive apparent clearance, which was lower in patients with mCRPC (1,550 L/h) versus healthy subjects (2,240 L/h), and by large apparent central (5,620 L) and peripheral (17,400 L) volumes of distribution. Abiraterone pharmacokinetics were similar in chemotherapy-pretreated and -naïve patients and were characterized by a high between- and within-subject variability [e.g., between-subject coefficient of variation (CV%) for relative bioavailability for the modified fasting state was 61.1 % and the CV% for within-subject variability was 71.3 %]. The fat content of food taken with Abiraterone acetate affected the bioavailability of Abiraterone. No factors beyond food intake and health status (healthy vs. mCRPC) impacted Abiraterone pharmacokinetics. Conclusions Based on the pharmacokinetics model, the recommended 1,000 mg/day of Abiraterone acetate resulted in similar Abiraterone exposure for patients with mCRPC regardless of prior chemotherapy. The fat content of food affected relative bioavailability of Abiraterone, though the extent of this effect is dependent on health status.

Fred Saad - One of the best experts on this subject based on the ideXlab platform.

  • clinical outcomes from androgen signaling directed therapy after treatment with Abiraterone acetate and prednisone in patients with metastatic castration resistant prostate cancer post hoc analysis of cou aa 302
    European Urology, 2017
    Co-Authors: Matthew R Smith, Karim Fizazi, Thian Kheoh, Dana E Rathkopf, Johann S De Bono, Neal D Shore, Peter F A Mulders, Eric J Small, Fred Saad, Peter De Porre
    Abstract:

    Abstract In the COU-AA-302 trial, Abiraterone acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling–directed therapies following Abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent Abiraterone acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6–not estimable) for subsequent Abiraterone acetate plus prednisone and 2.8 mo (range 1.8–not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent Abiraterone acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with Abiraterone acetate plus prednisone or enzalutamide for patients who progressed on Abiraterone acetate is associated with limited clinical benefit. Patient summary This analysis showed limited clinical benefit for subsequent Abiraterone acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with Abiraterone acetate plus prednisone. This analysis does not support prioritization of subsequent Abiraterone acetate plus prednisone or enzalutamide following initial therapy with Abiraterone acetate plus prednisone.

  • Clinical Outcomes from Androgen Signaling–directed Therapy after Treatment with Abiraterone Acetate and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302
    European urology, 2017
    Co-Authors: Matthew R Smith, Karim Fizazi, Dana E Rathkopf, Johann S De Bono, Neal D Shore, Peter F A Mulders, Eric J Small, Fred Saad, Thian Kheoh
    Abstract:

    Abstract In the COU-AA-302 trial, Abiraterone acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling–directed therapies following Abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent Abiraterone acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6–not estimable) for subsequent Abiraterone acetate plus prednisone and 2.8 mo (range 1.8–not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent Abiraterone acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with Abiraterone acetate plus prednisone or enzalutamide for patients who progressed on Abiraterone acetate is associated with limited clinical benefit. Patient summary This analysis showed limited clinical benefit for subsequent Abiraterone acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with Abiraterone acetate plus prednisone. This analysis does not support prioritization of subsequent Abiraterone acetate plus prednisone or enzalutamide following initial therapy with Abiraterone acetate plus prednisone.

  • Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer
    Clinical Pharmacokinetics, 2017
    Co-Authors: Charles J. Ryan, Matthew R Smith, Fred Saad, Peter De Porre, Thomas W. Griffin, Kim Stuyckens, An Vermeulen, Italo Poggesi, Youn C. Park, Partha Nandy
    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.

  • Abiraterone in the management of castration-resistant prostate cancer prior to chemotherapy
    Therapeutic advances in urology, 2015
    Co-Authors: Benjamin A. Gartrell, Fred Saad
    Abstract:

    The treatment armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has increased significantly over the past several years. Approved drugs associated with improved survival include androgen pathway-targeted agents (Abiraterone acetate and enzalutamide), chemotherapeutics (docetaxel and cabazitaxel), an autologous vaccine (sipuleucel-T) and a radiopharmaceutical (radium-223). Abiraterone acetate, a prodrug of Abiraterone, inhibits the CYP17A enzyme, a critical enzyme in androgen biosynthesis. Abiraterone has regulatory approval in mCRPC in both chemotherapy-naive patients and in the post-docetaxel setting based on results from two randomized phase III studies. In the COU-AA-302 trial, Abiraterone demonstrated significant improvement in the coprimary endpoints of radiographic progression-free survival and overall survival, as well as in a number of secondary endpoints including time until initiation of chemotherapy, time until opiate use for cancer-related pain, prostate-specific antigen progression-free survival and decline in performance status. Abiraterone is well-tolerated, although adverse events associated with this agent include abnormalities in liver function testing and mineralocorticoid-associated adverse events. This review evaluates the use of Abiraterone in mCRPC prior to the use of chemotherapy.

  • Population Pharmacokinetic Analysis of Abiraterone in Chemotherapy-Naïve and Docetaxel-Treated Patients with Metastatic Castration-Resistant Prostate Cancer
    Clinical Pharmacokinetics, 2014
    Co-Authors: Kim Stuyckens, Matthew R Smith, Charles J. Ryan, Fred Saad, Thomas W. Griffin, Xu Steven Xu, Margaret K. Yu, An Vermeulen, Partha Nandy, Italo Poggesi
    Abstract:

    Background and Objectives Abiraterone acetate, an androgen biosynthesis inhibitor, prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) in the pre- and post-chemotherapy setting as demonstrated by the pivotal phase III studies COU-AA-301 and COU-AA-302. We performed population pharmacokinetic analyses to estimate pharmacokinetic parameters after oral administration of 1,000 mg/day of Abiraterone acetate in patients with mCRPC, with or without prior chemotherapy, and after a single 1,000 mg dose in healthy volunteers. The study objectives were to determine consistency between patient populations and to characterize factors that may influence Abiraterone pharmacokinetics. Methods Studies in this analysis included COU-AA-302 (chemotherapy naïve); COU-AA-301 and COU-AA-006 (chemotherapy pretreated); and COU-AA-008, COU-AA-009, and COU-AA-014 (healthy subjects). A total of 4,627 plasma concentrations from 359 subjects (62 healthy volunteers, 297 patients) were analyzed using non-linear mixed-effects modeling. Results An Erlang-type absorption model with first-order elimination and three-transit compartments following sequential zero- and first-order processes was used to characterize Abiraterone pharmacokinetics. Absorption-related parameters were affected by food intake. Abiraterone pharmacokinetics were characterized by an extensive apparent clearance, which was lower in patients with mCRPC (1,550 L/h) versus healthy subjects (2,240 L/h), and by large apparent central (5,620 L) and peripheral (17,400 L) volumes of distribution. Abiraterone pharmacokinetics were similar in chemotherapy-pretreated and -naïve patients and were characterized by a high between- and within-subject variability [e.g., between-subject coefficient of variation (CV%) for relative bioavailability for the modified fasting state was 61.1 % and the CV% for within-subject variability was 71.3 %]. The fat content of food taken with Abiraterone acetate affected the bioavailability of Abiraterone. No factors beyond food intake and health status (healthy vs. mCRPC) impacted Abiraterone pharmacokinetics. Conclusions Based on the pharmacokinetics model, the recommended 1,000 mg/day of Abiraterone acetate resulted in similar Abiraterone exposure for patients with mCRPC regardless of prior chemotherapy. The fat content of food affected relative bioavailability of Abiraterone, though the extent of this effect is dependent on health status.

Thian Kheoh - One of the best experts on this subject based on the ideXlab platform.

  • clinical outcomes from androgen signaling directed therapy after treatment with Abiraterone acetate and prednisone in patients with metastatic castration resistant prostate cancer post hoc analysis of cou aa 302
    European Urology, 2017
    Co-Authors: Matthew R Smith, Karim Fizazi, Thian Kheoh, Dana E Rathkopf, Johann S De Bono, Neal D Shore, Peter F A Mulders, Eric J Small, Fred Saad, Peter De Porre
    Abstract:

    Abstract In the COU-AA-302 trial, Abiraterone acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling–directed therapies following Abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent Abiraterone acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6–not estimable) for subsequent Abiraterone acetate plus prednisone and 2.8 mo (range 1.8–not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent Abiraterone acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with Abiraterone acetate plus prednisone or enzalutamide for patients who progressed on Abiraterone acetate is associated with limited clinical benefit. Patient summary This analysis showed limited clinical benefit for subsequent Abiraterone acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with Abiraterone acetate plus prednisone. This analysis does not support prioritization of subsequent Abiraterone acetate plus prednisone or enzalutamide following initial therapy with Abiraterone acetate plus prednisone.

  • Clinical Outcomes from Androgen Signaling–directed Therapy after Treatment with Abiraterone Acetate and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302
    European urology, 2017
    Co-Authors: Matthew R Smith, Karim Fizazi, Dana E Rathkopf, Johann S De Bono, Neal D Shore, Peter F A Mulders, Eric J Small, Fred Saad, Thian Kheoh
    Abstract:

    Abstract In the COU-AA-302 trial, Abiraterone acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling–directed therapies following Abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent Abiraterone acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6–not estimable) for subsequent Abiraterone acetate plus prednisone and 2.8 mo (range 1.8–not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent Abiraterone acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with Abiraterone acetate plus prednisone or enzalutamide for patients who progressed on Abiraterone acetate is associated with limited clinical benefit. Patient summary This analysis showed limited clinical benefit for subsequent Abiraterone acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with Abiraterone acetate plus prednisone. This analysis does not support prioritization of subsequent Abiraterone acetate plus prednisone or enzalutamide following initial therapy with Abiraterone acetate plus prednisone.

  • Efficacy and Safety of Abiraterone Acetate in Elderly (75 Years or Older) Chemotherapy Naïve Patients with Metastatic Castration Resistant Prostate Cancer.
    The Journal of urology, 2015
    Co-Authors: Matthew R Smith, Arturo Molina, Thian Kheoh, Dana E Rathkopf, Peter F A Mulders, Joan Carles, Hendrik Van Poppel, Thomas W. Griffin, Charles J. Ryan
    Abstract:

    Purpose: Metastatic castration resistant prostate cancer primarily affects elderly men. In this post hoc analysis we investigated the safety and efficacy of Abiraterone acetate in elderly (age 75 years or greater) and younger (less than 75 years) patient subgroups at the prespecified interim analysis (55% of total overall survival events) for the COU-AA-302 (Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer) trial.Materials and Methods: Patients were stratified and randomized 1:1 to Abiraterone acetate 1,000 mg plus prednisone/prednisolone 5 mg twice daily (Abiraterone-prednisone) vs placebo plus prednisone/prednisolone 5 mg twice daily (prednisone alone). Co-primary end points were radiographic progression-free and overall survival. Median time to event and HR were estimated using the Kaplan-Meier method and a Cox model, respectively.Results: A total of 350 elderly patients treated with Abiraterone-prednisone had significant improvemen...

James Jiao - One of the best experts on this subject based on the ideXlab platform.

  • In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity.
    Drug metabolism and disposition: the biological fate of chemicals, 2016
    Co-Authors: Johan Monbaliu, Martha Gonzalez, James Jiao, Hans Stieltjes, Jan Snoeys, Apexa Bernard, Carlo Sensenhauser, Inneke Wynant, Johan W. Smit, Caly Chien
    Abstract:

    Abiraterone acetate, the prodrug of the cytochrome P450 C17 inhibitor Abiraterone, plus prednisone is approved for treatment of metastatic castration-resistant prostate cancer. We explored whether Abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and Abiraterone and its major metabolites, Abiraterone sulfate and Abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC50 values near or below the peak total concentrations observed in patients with metastatic castration-resistant prostate cancer (IC50 values: 1.3-3.0 µM, 1.6-2.9 µM, 0.044-0.15 µM, and 5.4-5.9 µM, respectively). CYP2C8 inhibition was reversible and time-independent. To explore the clinical relevance of the in vitro data, an open-label, single-center study was conducted comprising 16 healthy male subjects who received a single 15-mg dose of the CYP2C8 substrate pioglitazone on day 1 and again 1 hour after the administration of Abiraterone acetate 1000 mg on day 8. Plasma concentrations of pioglitazone, its active M-III (keto derivative) and M-IV (hydroxyl derivative) metabolites, and Abiraterone were determined for up to 72 hours after each dose. Abiraterone acetate increased exposure to pioglitazone; the geometric mean ratio (day 8/day 1) was 125 [90% confidence interval (CI), 99.9-156] for Cmax and 146 (90% CI, 126-171) for AUClast Exposure to M-III and M-IV was reduced by 10% to 13%. Plasma Abiraterone concentrations were consistent with previous studies. These results show that Abiraterone only weakly inhibits CYP2C8 in vivo.

  • food effects on Abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration resistant prostate cancer
    The Journal of Clinical Pharmacology, 2015
    Co-Authors: Kim N Chi, Scott North, Martha Gonzalez, Hans Stieltjes, Christian K Kollmannsberger, Apexa Bernard, Jennifer L Spratlin, Catherine Pankras, Lixian Peng, James Jiao
    Abstract:

    Food effect on Abiraterone pharmacokinetics and safety on Abiraterone acetate coadministration with low-fat or high-fat meals was examined in healthy subjects and metastatic castration-resistant prostate cancer (mCRPC) patients. Healthy subjects (n = 36) were randomized to Abiraterone acetate (single dose, 1000 mg) + low-fat meal, + high-fat meal, and fasted state. mCRPC patients received repeated doses (Abiraterone acetate 1000 mg + 5 mg prednisone twice daily; days 1–7) in a modified fasting state followed by Abiraterone acetate plus prednisone within 0.5 hours post–low-fat (n = 6) or high-fat meal (n = 18; days 8–14). In healthy subjects, geometric mean (GM) Abiraterone area under plasma concentration–time curve (AUC) increased ∼5- and ∼10-fold, respectively, with low-fat and high-fat meals versus fasted state (GM [coefficient of variation], 1942 [48] and 4077 [37] ng · h/mL vs 421 [67] ng · h/mL, respectively). In mCRPC patients, Abiraterone AUC was ∼2-fold higher with a high-fat meal and similar with a low-fat meal versus modified fasting state (GM [coefficient of variation]: 1992 [34] vs 973 [58] ng · h/mL and 1264 [65] vs 1185 [90] ng · h/mL, respectively). Adverse events (all grade ≤ 3) were similar, with high-fat/low-fat meals or fasted/modified fasting state. Short-term dosing with food did not alter Abiraterone acetate safety.

  • Pharmacokinetics of Abiraterone in healthy Japanese men: dose-proportionality and effect of food timing.
    Cancer chemotherapy and pharmacology, 2014
    Co-Authors: Kouichi Inoue, James Jiao, Hans Stieltjes, Apexa Bernard, Nicole Vaccaro, Akira Shishido, Caly Chien
    Abstract:

    Purpose Abiraterone acetate (AA) was recently approved for castration-resistant prostate cancer in Japan. Two phase 1 studies were conducted to assess the pharmacokinetics of Abiraterone after single-dose administration in Japanese healthy men and to evaluate the effects of food timing on Abiraterone pharmacokinetics after single-dose administration of AA in Japanese and Caucasian healthy men.

  • Impact on Abiraterone pharmacokinetics and safety: Open-label drug-drug interaction studies with ketoconazole and rifampicin.
    Clinical pharmacology in drug development, 2014
    Co-Authors: Apexa Bernard, James Jiao, Hans Stieltjes, Johan Monbaliu, Nicole Vaccaro, Milin Acharya, Ronald De Vries, Namphuong Tran, Caly Chien
    Abstract:

    We evaluated the impact of a strong CYP3A4 inhibitor, ketoconazole, and a strong inducer, rifampicin, on the pharmacokinetic (PK) exposure of Abiraterone in two studies in healthy men. All subjects received 1,000 mg of Abiraterone acetate on Days 1 and 14. Study A subjects (n = 20) received 400 mg ketoconazole on Days 11-16. Study B subjects (n = 19) received 600 mg rifampicin on Days 8-13. Serial PK sampling was done on Days 1 and 14. Study A: When given with ketoconazole, Abiraterone exposure increased by 9% for maximum plasma concentration (Cmax ) and 15% for area under the plasma concentration-time curve from 0 to time of the last quantifiable concentration (AUClast ) and AUC from time 0 to infinity (AUC∞ ) compared to Abiraterone acetate alone. Study B: When given with rifampicin, Abiraterone exposure was reduced to 45% for Cmax and AUC∞ and to 42% for AUClast compared to Abiraterone acetate alone. Ketoconazole had no clinically meaningful impact on Abiraterone exposure. Rifampicin decreased Abiraterone exposure by half. Hence, strong CYP3A4 inducers should be avoided or used with careful evaluation of clinical efficacy when administered with Abiraterone acetate.

  • Single‐dose pharmacokinetic studies of Abiraterone acetate in men with hepatic or renal impairment
    The Journal of Clinical Pharmacology, 2014
    Co-Authors: Thomas Marbury, Eric Lawitz, C M Haqq, Robert Stonerock, Martha Gonzalez, James Jiao, Jim Breeding, Peter Verboven, Hans Stieltjes
    Abstract:

    Three open-label, single-dose studies investigated the impact of hepatic or renal impairment on Abiraterone acetate pharmacokinetics and safety/tolerability in non-cancer patients. Patients (n = 8 each group) with mild/moderate hepatic impairment or end-stage renal disease (ESRD), and age-, BMI-matched healthy controls received a single oral 1,000 mg Abiraterone acetate (tablet dose); while patients (n = 8 each) with severe hepatic impairment and matched healthy controls received 125- and 2,000-mg Abiraterone acetate (suspension doses), respectively (systemic exposure of Abiraterone acetate suspension is approximately half to that of tablet formulation). Blood was sampled at specified timepoints up to 72 or 96 hours postdose to measure plasma Abiraterone concentrations. Abiraterone exposure was comparable between healthy controls and patients with mild hepatic impairment or ESRD, but increased by 4-fold in patients with moderate hepatic impairment. Despite a 16-fold reduction in dose, Abiraterone exposure in patients with severe hepatic impairment was about 22% and 44% of the Cmax and AUC∞ of healthy controls, respectively. These results suggest that Abiraterone pharmacokinetics were not changed markedly in patients with ESRD or mild hepatic impairment. However, the capacity to eliminate Abiraterone was substantially compromised in patients with moderate or severe hepatic impairment. A single-dose administration of Abiraterone acetate was well-tolerated.

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  • In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity.
    Drug metabolism and disposition: the biological fate of chemicals, 2016
    Co-Authors: Johan Monbaliu, Martha Gonzalez, James Jiao, Hans Stieltjes, Jan Snoeys, Apexa Bernard, Carlo Sensenhauser, Inneke Wynant, Johan W. Smit, Caly Chien
    Abstract:

    Abiraterone acetate, the prodrug of the cytochrome P450 C17 inhibitor Abiraterone, plus prednisone is approved for treatment of metastatic castration-resistant prostate cancer. We explored whether Abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and Abiraterone and its major metabolites, Abiraterone sulfate and Abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC50 values near or below the peak total concentrations observed in patients with metastatic castration-resistant prostate cancer (IC50 values: 1.3-3.0 µM, 1.6-2.9 µM, 0.044-0.15 µM, and 5.4-5.9 µM, respectively). CYP2C8 inhibition was reversible and time-independent. To explore the clinical relevance of the in vitro data, an open-label, single-center study was conducted comprising 16 healthy male subjects who received a single 15-mg dose of the CYP2C8 substrate pioglitazone on day 1 and again 1 hour after the administration of Abiraterone acetate 1000 mg on day 8. Plasma concentrations of pioglitazone, its active M-III (keto derivative) and M-IV (hydroxyl derivative) metabolites, and Abiraterone were determined for up to 72 hours after each dose. Abiraterone acetate increased exposure to pioglitazone; the geometric mean ratio (day 8/day 1) was 125 [90% confidence interval (CI), 99.9-156] for Cmax and 146 (90% CI, 126-171) for AUClast Exposure to M-III and M-IV was reduced by 10% to 13%. Plasma Abiraterone concentrations were consistent with previous studies. These results show that Abiraterone only weakly inhibits CYP2C8 in vivo.

  • food effects on Abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration resistant prostate cancer
    The Journal of Clinical Pharmacology, 2015
    Co-Authors: Kim N Chi, Scott North, Martha Gonzalez, Hans Stieltjes, Christian K Kollmannsberger, Apexa Bernard, Jennifer L Spratlin, Catherine Pankras, Lixian Peng, James Jiao
    Abstract:

    Food effect on Abiraterone pharmacokinetics and safety on Abiraterone acetate coadministration with low-fat or high-fat meals was examined in healthy subjects and metastatic castration-resistant prostate cancer (mCRPC) patients. Healthy subjects (n = 36) were randomized to Abiraterone acetate (single dose, 1000 mg) + low-fat meal, + high-fat meal, and fasted state. mCRPC patients received repeated doses (Abiraterone acetate 1000 mg + 5 mg prednisone twice daily; days 1–7) in a modified fasting state followed by Abiraterone acetate plus prednisone within 0.5 hours post–low-fat (n = 6) or high-fat meal (n = 18; days 8–14). In healthy subjects, geometric mean (GM) Abiraterone area under plasma concentration–time curve (AUC) increased ∼5- and ∼10-fold, respectively, with low-fat and high-fat meals versus fasted state (GM [coefficient of variation], 1942 [48] and 4077 [37] ng · h/mL vs 421 [67] ng · h/mL, respectively). In mCRPC patients, Abiraterone AUC was ∼2-fold higher with a high-fat meal and similar with a low-fat meal versus modified fasting state (GM [coefficient of variation]: 1992 [34] vs 973 [58] ng · h/mL and 1264 [65] vs 1185 [90] ng · h/mL, respectively). Adverse events (all grade ≤ 3) were similar, with high-fat/low-fat meals or fasted/modified fasting state. Short-term dosing with food did not alter Abiraterone acetate safety.

  • Pharmacokinetics of Abiraterone in healthy Japanese men: dose-proportionality and effect of food timing.
    Cancer chemotherapy and pharmacology, 2014
    Co-Authors: Kouichi Inoue, James Jiao, Hans Stieltjes, Apexa Bernard, Nicole Vaccaro, Akira Shishido, Caly Chien
    Abstract:

    Purpose Abiraterone acetate (AA) was recently approved for castration-resistant prostate cancer in Japan. Two phase 1 studies were conducted to assess the pharmacokinetics of Abiraterone after single-dose administration in Japanese healthy men and to evaluate the effects of food timing on Abiraterone pharmacokinetics after single-dose administration of AA in Japanese and Caucasian healthy men.

  • Impact on Abiraterone pharmacokinetics and safety: Open-label drug-drug interaction studies with ketoconazole and rifampicin.
    Clinical pharmacology in drug development, 2014
    Co-Authors: Apexa Bernard, James Jiao, Hans Stieltjes, Johan Monbaliu, Nicole Vaccaro, Milin Acharya, Ronald De Vries, Namphuong Tran, Caly Chien
    Abstract:

    We evaluated the impact of a strong CYP3A4 inhibitor, ketoconazole, and a strong inducer, rifampicin, on the pharmacokinetic (PK) exposure of Abiraterone in two studies in healthy men. All subjects received 1,000 mg of Abiraterone acetate on Days 1 and 14. Study A subjects (n = 20) received 400 mg ketoconazole on Days 11-16. Study B subjects (n = 19) received 600 mg rifampicin on Days 8-13. Serial PK sampling was done on Days 1 and 14. Study A: When given with ketoconazole, Abiraterone exposure increased by 9% for maximum plasma concentration (Cmax ) and 15% for area under the plasma concentration-time curve from 0 to time of the last quantifiable concentration (AUClast ) and AUC from time 0 to infinity (AUC∞ ) compared to Abiraterone acetate alone. Study B: When given with rifampicin, Abiraterone exposure was reduced to 45% for Cmax and AUC∞ and to 42% for AUClast compared to Abiraterone acetate alone. Ketoconazole had no clinically meaningful impact on Abiraterone exposure. Rifampicin decreased Abiraterone exposure by half. Hence, strong CYP3A4 inducers should be avoided or used with careful evaluation of clinical efficacy when administered with Abiraterone acetate.

  • Single‐dose pharmacokinetic studies of Abiraterone acetate in men with hepatic or renal impairment
    The Journal of Clinical Pharmacology, 2014
    Co-Authors: Thomas Marbury, Eric Lawitz, C M Haqq, Robert Stonerock, Martha Gonzalez, James Jiao, Jim Breeding, Peter Verboven, Hans Stieltjes
    Abstract:

    Three open-label, single-dose studies investigated the impact of hepatic or renal impairment on Abiraterone acetate pharmacokinetics and safety/tolerability in non-cancer patients. Patients (n = 8 each group) with mild/moderate hepatic impairment or end-stage renal disease (ESRD), and age-, BMI-matched healthy controls received a single oral 1,000 mg Abiraterone acetate (tablet dose); while patients (n = 8 each) with severe hepatic impairment and matched healthy controls received 125- and 2,000-mg Abiraterone acetate (suspension doses), respectively (systemic exposure of Abiraterone acetate suspension is approximately half to that of tablet formulation). Blood was sampled at specified timepoints up to 72 or 96 hours postdose to measure plasma Abiraterone concentrations. Abiraterone exposure was comparable between healthy controls and patients with mild hepatic impairment or ESRD, but increased by 4-fold in patients with moderate hepatic impairment. Despite a 16-fold reduction in dose, Abiraterone exposure in patients with severe hepatic impairment was about 22% and 44% of the Cmax and AUC∞ of healthy controls, respectively. These results suggest that Abiraterone pharmacokinetics were not changed markedly in patients with ESRD or mild hepatic impairment. However, the capacity to eliminate Abiraterone was substantially compromised in patients with moderate or severe hepatic impairment. A single-dose administration of Abiraterone acetate was well-tolerated.

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