Abstract A194: A QT/QTc and multi-dose pharmacokinetic (PK) study of abiraterone acetate (AA) plus prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Bibliographic record
Abstract
Abstract Background: AA is the prodrug of abiraterone (A), an androgen biosynthesis inhibitor that selectively inhibits CYP17, thereby blocking testicular, adrenal, and prostatic intratumoral androgen biosynthesis. In a phase 3 study, AA+P demonstrated survival improvements in post-docetaxel mCRPC pts (De Bono ESMO 2010). ADT with an LHRH analog (LHRHa) has been associated with median QTc interval prolongation of 9–21 msec (Garnick ASCO 2004). Primary objective: effects of AA+P on QT/QTc interval duration in mCRPC pts receiving LHRHa. Secondary objectives: pharmacokinetics (PK) of AA and abiraterone (A) after single/multiple doses of AA. Methods: In this open-label, single-arm phase 1b study (COU-AA-006/NCT00910754), 33 mCRPC pts with disease progression after failure of GnRH hormone therapy, a PSA ≥2 ng/mL and ≤1 course of prior chemotherapy, received AA 1000mg orally QD + P 5mg orally BID. ECGs were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle (C)1 Day (D)-1. Serial ECG recordings and time-matched PK blood samples were collected over 24 hrs on C1D1 and C2D1. Serial PK blood samples were also collected over 24 hrs on C1D8. Results: After AA administration, the upper bound of the 2-sided 90% CI for the mean baseline-adjusted QTcF change was <10 msec; no subjects discontinued due to QTc prolongation or AEs. Most AA plasma concentrations were below the quantification limit; thus AA PK analysis was not performed. A linear mixed-effects model showed no apparent relationship between change in QTcF and A plasma concentrations (estimated slope [90%CI): 0.0031 [−0.0040, 0.0102]). Exposure to A after multiple AA dosing on C1D8 and C2D1 increased versus exposure after single dose on C1D1; accumulation ratios for C1D8 (1.8–2.0) and C2D1 (2.0–2.2) were similar. The most commonly reported treatment-emergent AE (TEAE) was dizziness (12%); all TEAEs were grade 1; except 1 grade 3 AE (increased ALP) with no grade 4 TEAEs. Conclusions: There is no significant effect of AA+P on the cardiac QT/QTc interval in mCRPC pts. No relationship between change in QTcF and A plasma concentration was observed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A194.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".