A Phase 1 Study to Assess the Effect of Food on the Pharmacokinetics (PK) and Gastrointestinal (GI) Tolerability of Selumetinib in Adolescents with Neurofibromatosis Type 1 (NF1)-Related Plexiform Neurofibromas (PN)
Bibliographic record
Abstract
Background/Purpose: Selumetinib is a MEK1/2 inhibitor approved for pediatric patients with NF1 and symptomatic, inoperable PN in regions including EU (EMA, aged ≥3 years). The aim of this study was to evaluate the effect of a low-fat meal on steady-state exposure and GI tolerability in adolescents with NF1 and inoperable PN to confirm a recommendation for dosing selumetinib with food by a Ph 1 study (NCT05101148). Methods: Eligible patients aged ≥12 to <18 years received selumetinib 25 mg/m 2 two times daily for one cycle (28 days) with a low-fat meal according to FDA guidance (T1; fed C1), then in a fasted state for one cycle (T2; fasted C1) following 1-week washout. T2 continued beyond one cycle until the end of the study or dose-adjusted selumetinib in a fed state (T3), if required. 1° endpoints were AUC 0–12,ss , GI adverse events (AEs; CTCAE v5.0), and GI concomitant medications in fed versus fasted state. 2° endpoints included other PK parameters and safety. Results: Twenty-four participants received selumetinib; 19 were evaluable for fed versus fasted paired PK comparison. Mean duration of exposure for fed and fasted states was 28.3 (SD 1.1) and 28.3 (SD 3.0) days, respectively. Steady-state extent of absorption was similar for fed versus fasted (AUC 0–12,ss geometric mean ratio [GMR] 0.919; lower one-sided 90% CI bound 0.841). Fed-state C max was reduced (GMR 0.763; lower 1-sided 90% CI bound 0.667) and time to C max was delayed (34 minutes; 90% CI 28, 60; Figure 1) versus fasted state. Similar number of subjects experienced GI AEs (fed C1, 29.2%; fasted C1, 33.3%). GI PROs were consistent between fed C1 versus fasted C1. Overall use of concomitant GI medications was low. No new safety signals were identified. Conclusion: At steady state, dosing selumetinib with a low-fat meal delayed absorption rate and lowered C max but had no clinically significant effect (<30% AUC 0–12,ss reduction) on extent of absorption and GI tolerability. Thus, dose adjustment is unlikely required. This study shows dosing selumetinib with a low-fat meal has no significant impact on AUC or GI tolerability. Publication History Article published online: 13 November 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.003 | 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".