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

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, Neal D Shore, Thian Kheoh, Fred Saad, Dana E Rathkopf, Peter F A Mulders, Johann S De Bono, Eric J Small, Karim Fizazi, 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, Neal D Shore, Fred Saad, Dana E Rathkopf, Peter F A Mulders, Johann S De Bono, Eric J Small, Karim Fizazi, 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, Italo Poggesi, An Vermeulen, 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.

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, Neal D Shore, Thian Kheoh, Fred Saad, Dana E Rathkopf, Peter F A Mulders, Johann S De Bono, Eric J Small, Karim Fizazi, 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, Neal D Shore, Fred Saad, Dana E Rathkopf, Peter F A Mulders, Johann S De Bono, Eric J Small, Karim Fizazi, 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, Thian Kheoh, Dana E Rathkopf, Peter F A Mulders, Joan Carles, Hendrik Van Poppel, Thomas W. Griffin, Arturo Molina, 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 (Abirateroneprednisone) 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 Abirateroneprednisone 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, Hans Stieltjes, Martha Gonzalez, James Jiao, 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, Hans Stieltjes, Martha Gonzalez, Scott North, 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, Hans Stieltjes, James Jiao, 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.

Hans Stieltjes – 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, Hans Stieltjes, Martha Gonzalez, James Jiao, 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, Hans Stieltjes, Martha Gonzalez, Scott North, 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, Hans Stieltjes, James Jiao, 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.