Concentration‐QTc analysis of soticlestat in healthy adults: An alternative to a thorough QT study
Bibliographic record
Abstract
AIM: This study aimed to examine the cardiac and overall safety and pharmacokinetic (PK) profiles of soticlestat (TAK-935), an oral, first-in-class selective cholesterol 24-hydroxylase inhibitor. METHODS: Data came from a randomised, phase 1 study of soticlestat in 33 healthy Japanese adults (NCT04461483); 24 adults in Part 1 (single-dose soticlestat 200-1200 mg or placebo) and 9 in Part 2 (soticlestat 100-300 mg twice daily or placebo for 21 days). PK sample collection was paired with 12-lead electrocardiogram data from continuous Holter recordings. The concentration-QTc relationship was analysed using a linear mixed-effects model. QTc prolongation safety margins were determined for two scenarios of calculated high clinical exposures: scenario 1 (NCT05064449) involved coadministration of single-dose soticlestat 300 mg with itraconazole or mefenamic acid and scenario 2 (NCT05098054) involved single-dose soticlestat 300 mg administration in participants with mild/moderate hepatic impairment (implementing a 3-fold dose reduction for moderate severity). RESULTS: Based on concentration-QTc analysis, placebo-corrected change-from-baseline QT values (90% confidence intervals), corrected for heart rate (Fridericia's method), were 0.94 ms (-2.35, 4.23) for soticlestat and 0.63 ms (-3.15, 4.41) for its N-oxide metabolite plasma concentrations at therapeutic doses (soticlestat 300 mg twice daily); safety margins were >2-fold for scenarios of calculated high clinical exposures. No (Part 1) and five (83.3%; Part 2) participants experienced treatment-emergent adverse events (all mild). CONCLUSION: There was no evidence for QT prolongation with soticlestat at therapeutic doses or in two scenarios of high clinical exposures, which resulted in regulatory agencies waiving requirements of a thorough QT study. Safety/PK findings aligned with previous soticlestat clinical studies.
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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 | 0.004 | 0.005 |
| 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 | 0.001 |
| 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".