Comparison of the Pharmacokinetics of the Phase II and Phase III Capsule Formulations of Selumetinib and the Effects of Food on Exposure: Results From Two Randomized Crossover Trials in Healthy Male Subjects

Tomkinson, Helen; McBride, Eileen; Martín, Paul; Lisbon, Eleanor; Dymond, Angela W.; Cantarini, Mireille; So, Karen; Holt, David

doi:10.1016/j.clinthera.2017.08.022

Cited by 12 publications

(36 citation statements)

References 19 publications

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“…For the capsule formulation, the absorption of selumetinib (T max ) was also prolonged in the fed state versus the fasted state by ~0.9 h. A reduction (60%) in selumetinib C max was observed with the capsule formulation in the fed state versus the fasted state, which is similar to that observed in previous studies. 9 , 12 [Correction added on 23 March 2022, after first online publication: Difference in Tmax values for fed vs fasted state for capsule formulation has been corrected to ~0.9 h]. Furthermore, a 38% reduction in AUC occurred with the capsule formulation in the fed versus fasted state.…”

Section: Discussionmentioning

confidence: 99%

“…Food effect on selumetinib when dosed as capsules was previously evaluated in other clinical trials, including clinical pharmacology food effect studies in healthy volunteers (NCT01974349) and patients with advanced solid malignancies (NCT00710515). 9 , 12 In a phase I trial investigating whether a high‐fat meal influenced the rate and extent of selumetinib capsule absorption in patients with advanced solid malignancies, selumetinib decreased maximum plasma concentration (C max ) by 62% and diminished area under the plasma drug concentration‐time curve (AUC) by 19%. 9 In healthy volunteers, a mean reduction of both selumetinib C max by 50% and AUC by 16% was observed when selumetinib was administered with a high‐fat meal, although the data on the clinical significance of these reductions were not available.…”

Section: Introductionmentioning

confidence: 99%

“…The two aforementioned clinical studies of a high‐fat meal in adult patients with cancer and adult healthy volunteers demonstrated that food reduces peak selumetinib plasma concentrations by ~50–60%, with only a minimal decrease (<20%) in overall exposure, reflecting slower absorption compared with a fasted state. 9 , 12 As selumetinib is dosed twice daily, it would be challenging to restrict access to food in children. Therefore, we conducted a clinical study in adult healthy volunteers to investigate the food effect using a low‐fat, low‐calorie meal (~400 kcal), akin to a light meal or snack versus fasted conditions.…”

Section: Introductionmentioning

confidence: 99%

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Effect of food on capsule and granule formulations of selumetinib

Cohen-Rabbie

Mattinson

et al. 2022

Clinical Translational Sci

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Selumetinib is an oral, potent, and highly selective allosteric MEK1/2 inhibitor approved for the treatment of pediatric patients (aged ≥2 years) with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. A granule formulation of selumetinib is under development to improve dosing precision for younger pediatric patients who may be unable to swallow capsules. This phase I crossover study investigated the effect of food on the pharmacokinetic (PK) properties of selumetinib capsule and granule formulations. Healthy male volunteers were randomized to receive selumetinib granules (25 mg) or capsules (50 mg [2 × 25 mg]) under fasted or fed conditions (a low‐fat meal). Plasma concentrations and PK parameters were determined less than or equal to 48 h postdose. Safety and tolerability were assessed. Across 24 volunteers, selumetinib was absorbed quickly, with a time to maximum concentration (T max ) ranging from ~1–3 h. Geometric mean ratios (90% confidence interval [CI]) for maximum plasma concentration (C max ) in the fed versus fasted state were 0.61 (90% CI 0.51–0.72) and 0.40 (90% CI 0.33–0.48) for the granule and capsule formulations, respectively, whereas geometric mean ratios (90% CI) for area under the plasma drug concentration‐time curve in the fed versus fasted state were 0.97 (90% CI 0.91–1.02) and 0.62 (90% CI 0.55–0.70), respectively. Levels of less than 10% conversion to the N‐desmethyl selumetinib metabolite were observed. Selumetinib was well‐tolerated, with only a few adverse events of mild intensity reported. Selumetinib administration with a low‐fat meal resulted in lower C max and longer T max for both formulations versus fasted conditions. However, area under the curve for selumetinib granules was similar under fasted and fed conditions. Overall, these findings support further development of this formulation for pediatric patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of food on capsule and granule formulations of selumetinib

Cohen-Rabbie

Mattinson

et al. 2022

Clinical Translational Sci

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“…Drug doses of selumetinib and trametinib were chosen based on IC50 results from our previous experiments [24]. Selected concentrations for these experiments are in keeping with steady state serum levels (selumetinib 2 μM and trametinib 30 nM) reported for these drugs in humans [26, 27]. Phase contrast images of cells were taken every 6-h for 4–5 days.…”

Section: Methodsmentioning

confidence: 99%

Markers of MEK inhibitor resistance in low-grade serous ovarian cancer: EGFR is a potential therapeutic target

et al. 2019

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BackgroundAlthough low-grade serous ovarian cancer (LGSC) is rare, case-fatality rates are high as most patients present with advanced disease and current cytotoxic therapies are not overly effective. Recognizing that these cancers may be driven by MAPK pathway activation, MEK inhibitors (MEKi) are being tested in clinical trials. LGSC respond to MEKi only in a subgroup of patients, so predictive biomarkers and better therapies will be needed.MethodsWe evaluated a number of patient-derived LGSC cell lines, previously classified according to their MEKi sensitivity. Two cell lines were genomically compared against their matching tumors samples. MEKi-sensitive and MEKi-resistant lines were compared using whole exome sequencing and reverse phase protein array. Two treatment combinations targeting MEKi resistance markers were also evaluated using cell proliferation, cell viability, cell signaling, and drug synergism assays.ResultsLow-grade serous ovarian cancer cell lines recapitulated the genomic aberrations from their matching tumor samples. We identified three potential predictive biomarkers that distinguish MEKi sensitive and resistant lines: KRAS mutation status, and EGFR and PKC-alpha protein expression. The biomarkers were validated in three newly developed LGSC cell lines. Sub-lethal combination of MEK and EGFR inhibition showed drug synergy and caused complete cell death in two of four MEKi-resistant cell lines tested.ConclusionsKRAS mutations and the protein expression of EGFR and PKC-alpha should be evaluated as predictive biomarkers in patients with LGSC treated with MEKi. Combination therapy using a MEKi with EGFR inhibition may represent a promising new therapy for patients with MEKi-resistant LGSC.Electronic supplementary materialThe online version of this article (10.1186/s12935-019-0725-1) contains supplementary material, which is available to authorized users.

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“…Selumetinib (AZD6244, ARRY142886) is a potent and selective allosteric MEK1/2 inhibitor. 10 , 11 MEK1/2 is a critical component of the RAS/RAF/MEK/ERK pathway, and its activation is essential for cell proliferation and central to drive the growth and progression of cancer. 12 , 13 In fact, owing to the complexity of hard-to-treat diseases such as cancer, current developments have gently shifted from a focus on monotherapy to combined or multiple therapies since the synergy of therapeutic agents or techniques could give rise to superadditive therapeutic effects.…”

Section: Introductionmentioning

confidence: 99%

A Combined Antitumor Strategy Mediated by a New Targeted Nanosystem to Hepatocellular Carcinoma

Farinha¹,

Migawa²,

Sarmento‐Ribeiro³

et al. 2021

IJN

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Background: Hepatocellular carcinoma (HCC) is one of the main causes of cancer-related death. Sorafenib, which is the first-line therapy for this disease, is associated with reduced therapeutic efficacy that could potentially be overcome by combination with selumetinib. In this context, the main goal of this work was to develop a new nanosystem, composed of a polymeric core coated by a lipid bilayer containing the targeting ligand GalNAc, to specifically and efficiently co-deliver both drugs into HCC cells, in order to significantly increase their therapeutic efficacy. Methods: The physicochemical characterization of hybrid nanosystems (HNP) and their components was performed by dynamic light scattering, zeta potential, matrix-assisted laser desorption ionization -time of flight mass spectroscopy, and transmission electron microscopy. Cellular binding, uptake and specificity of HNP were evaluated through flow cytometry and confocal microscopy. The therapeutic activity was evaluated namely through: cell viability by the Alamar Blue assay; cell death by flow cytometry using FITC-Annexin V; caspases activity by luminescence; mitochondrial membrane potential by flow cytometry; and molecular target levels by Western blot. Results: The obtained data show that these hybrid nanosystems present high stability and loading capacity of both drugs, and suitable physicochemical properties, namely in terms of size and surface charge. Moreover, the generated formulation allows to circumvent drug resistance and presents high specificity, promoting great cell death levels in HCC cells, but not in non-tumor cells. This potentiation of the antitumor effect of co-loaded drugs was carried out by an increased programmed cell death, being associated with a strong reduction in the mitochondrial membrane potential, a significant increase in the activity of caspases 3/7 and caspase 9, and much greater number of annexin V-positive cells. Conclusion:The developed formulation resulted in a high and synergistic antitumor effect, revealing a translational potential to improve therapeutic approaches against HCC.

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Comparison of the Pharmacokinetics of the Phase II and Phase III Capsule Formulations of Selumetinib and the Effects of Food on Exposure: Results From Two Randomized Crossover Trials in Healthy Male Subjects

Cited by 12 publications

References 19 publications

Effect of food on capsule and granule formulations of selumetinib

Effect of food on capsule and granule formulations of selumetinib

Markers of MEK inhibitor resistance in low-grade serous ovarian cancer: EGFR is a potential therapeutic target

A Combined Antitumor Strategy Mediated by a New Targeted Nanosystem to Hepatocellular Carcinoma

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