Population pharmacokinetic analysis of abiraterone acetate in healthy volunteers and chemotherapy-naive and chemotherapy-pretreated metastatic castration-resistant prostate cancer patients.
Bibliographic record
Abstract
58 Background: Abiraterone acetate (AA) is an effective therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). AA is metabolized to abiraterone, an androgen biosynthesis inhibitor. We performed population pharmacokinetic (PK) analyses to estimate PK parameters after a 1,000 mg/d oral dose of AA in patients with mCRPC with and without prior chemotherapy and after a one-time 1,000 mg dose in healthy volunteers, to determine consistency between groups. Methods: Studies included in analysis: COU-AA-302 (pre-chemotherapy mCRPC); COU-AA-301 and COU-AA-006 (post-docetaxel mCRPC); and COU-AA-008, COU-AA-009, and COU-AA-014 (healthy subjects). A total of 4,627 plasma concentrations from 360 subjects were analyzed using nonlinear mixed-effects modeling. Results: A two-compartment model with three-transit compartments following sequential zero-first order kinetics was used to characterize the systemic absorption of abiraterone. Absorption-related parameters were affected by food intake. Abiraterone PK was characterized by an extensive apparent clearance, which was lower in patients with mCRPC (1505 L/h) compared with healthy subjects (2240 L/h), and by large apparent central (5630 L) and peripheral volumes of distribution (17,400 L). PK of abiraterone was similar in chemotherapy-naïve and chemotherapy-pretreated patients and was characterized by a relatively high between- and within-subject variability (eg, between-subject coefficient of variation [CV%] for relative bioavailability in the clinical studies was 61.1% and the CV% for within-subject variability was 71.3%). No factors other than food intake and patient-healthy volunteer status impacted PK. Conclusions: Based on this population PK model, the recommended 1,000 mg/d dose of AA results in similar abiraterone exposure for patients with mCRPC regardless of prior chemotherapy status. The food effect on absorption-related parameters in this analysis confirms current dosing instructions for AA. Clinical trial information: NCT00638690, NCT00887198.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".