Neuropediatrics 2023; 54(S 01): S1-S32
DOI: 10.1055/s-0043-1777199
Neue Therapieoptionen in der Neuropädiatrie

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)

A. Nguyen Chi
1   Alexion, AstraZeneca Rare Disease Germany, Medical Affairs, Munich, Deutschland
,
M. Wysocki
2   Department of Pediatric Hematology and Oncology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University Torun, Jurasz University Hospital 1, Bydgoszcz, Polen
,
M. Learoyd
3   AstraZeneca UK, Clinical Pharmacology and Safety Sciences R&D, Cambridge, Vereinigtes Königreich
,
P. Sun
4   Clinical Development, Alexion AstraZeneca Rare Disease UK, NF and Bone Metabolism Therapeutic Area, Cambridge, Vereinigtes Königreich
,
K. So
4   Clinical Development, Alexion AstraZeneca Rare Disease UK, NF and Bone Metabolism Therapeutic Area, Cambridge, Vereinigtes Königreich
,
A. Evans
4   Clinical Development, Alexion AstraZeneca Rare Disease UK, NF and Bone Metabolism Therapeutic Area, Cambridge, Vereinigtes Königreich
,
F. Lai
5   Quantitative Sciences, Alexion, AstraZeneca Rare Disease USA, Boston, Vereinigte Staaten von Amerika
,
H. Salvador Hernàndez
6   Sant Joan de Déu Barcelona Hospital, Barcelona, Spanien
,
D. Viskochil
7   Department of Pediatrics, University of Utah, Salt Lake City, Vereinigte Staaten von Amerika
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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/m2 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 AUC0–12,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 (AUC0–12,ss geometric mean ratio [GMR] 0.919; lower one-sided 90% CI bound 0.841). Fed-state Cmax was reduced (GMR 0.763; lower 1-sided 90% CI bound 0.667) and time to Cmax 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 Cmax but had no clinically significant effect (<30% AUC0–12,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

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