Effect of food on exposure to napabucasin: Data from two phase I studies.
Bibliographic record
Abstract
477 Background: Napabucasin is an orally-administered NAD(P)H quinone dehydrogenase 1–bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including STAT3. Methods: Food effects on napabucasin pharmacokinetics were evaluated in two studies: one at two sites in Japan (Study 1; JapicCTI-205447) and the other at two sites in the US and three in Canada (Study 2; NCT01775423). Study 1 enrolled healthy Japanese male volunteers (HJMV) who received napabucasin 480 mg (formula 2) per sequential design — fasting on Day (D) 1 followed by a Japanese diet (JD) on D8 — with a 6-D intervening washout. In Study 2, patients (pts) with advanced malignancies received napabucasin 500 mg (formula 1) on D1 in the fasted state, then napabucasin 500 mg (formula 2) on D4 and D8 with a high-fat breakfast [HFB] or in the fasted state per the randomized sequence per crossover design. Results: In Study 1, mean plasma napabucasin levels 6–10 h after napabucasin 480 mg administration were higher in fed (JD) vs fasted states; in the fed state, Cmax increased by 15% and AUClast by ~60% (Table), while tmax decreased by ~1.4 hours. Adverse events (AEs) in Study 1 occurred in 5/6 (83.3%) HJMVs (fasted, n=3; fed, n=5; all grade [gr] 1). In Study 2, mean concentration profiles were comparable in fasted and fed (HFB) states for napabucasin 500 mg. When comparing fasted and fed states, Cmax increased by 21% and AUClast by 39% in the fed state (Table). Interpatient variability was high: geometric CV% for CL/F was 75.9% (fed) and 141% (fasted). AEs in Study 2 occurred in 68% (17/25) of fasted pts (gr 1: n=7; gr 2: n=8; gr 3, n=2) and 50% (7/14) of pts fed an HFB (gr 1: n=2; gr 2: n=3; gr 3, n=2). Conclusions: In HJMVs, napabucasin 480 mg administered with a JD increased exposure (Cmax; AUClast; AUCinf) and decreased tmax vs the fasted state. In pts with advanced malignancies, napabucasin 500 mg administered with an HFB increased exposure (Cmax; AUClast) vs the fasted state. These exposure increases are not considered to be of clinical relevance. Clinical trial information: JapicCTI-205447; NCT01775423. [Table: see text]
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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 | 0.003 | 0.003 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.003 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
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".