Comparison of exposure response relationship of atrasentan between <scp>N</scp> orth <scp>A</scp> merican and <scp>A</scp> sian populations
Bibliographic record
Abstract
Aims The selective endothelin ( ET ) A receptor antagonist atrasentan has been shown to lower albuminuria in N orth A merican and A sian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between N orth A merican and A sian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to atrasentan. Materials and methods Two 12‐week double‐blind randomised controlled trials were performed with atrasentan 0.75 or 1.25 mg/d vs placebo in patients with type 2 diabetes and nephropathy. The efficacy endpoint was the percentage change in albuminuria. Bodyweight change, a proxy of fluid retention, was used as a safety endpoint. Pharmacodynamics were determined in A sians ( N = 77) and N orth A mericans ( N = 134). Atrasentan plasma concentration was measured in 161 atrasentan‐treated patients. Results Mean albuminuria reduction in Asian, compared to N orth A merican, patients was, respectively, −34.4% vs −26.3% for 0.75 mg/d ( P = .44) and −48.0% vs −28.9% for 1.25 mg/d ( P = .035). Bodyweight gain did not differ between N orth A merican and A sian populations. Atrasentan plasma concentrations were higher in A sians compared to N orth A mericans and correlated with albuminuria response (7.2% albuminuria reduction per doubling atrasentan concentration; P = .024). Body surface area (β = −1.09 per m 2 ; P < .001) and bilirubin, as a marker of hepatic organic anion transporter activity, (β = 0.69 per mg/ dL increment; P = .010) were independent determinants of atrasentan plasma concentration; correction by body surface area and bilirubin left no significant difference in plasma concentration between A sian and N orth A merican populations. Conclusion The higher exposure and albuminuria reduction of atrasentan in A sian patients is not associated with more fluid retention, suggesting that A sian patients are less sensitive to atrasentan‐induced sodium retention.
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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 | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| 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) | 0.002 | 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".