Pharmacokinetics of a Single Oral Dose of the MEK1/2 Inhibitor Selumetinib in Subjects With End‐Stage Renal Disease or Varying Degrees of Hepatic Impairment Compared With Healthy Subjects

Dymond, Angela W.; Martín, Paul; So, Karen; Huang, Yifan; Severin, Paul; Holmes, Victoria; Mariani, G; Marbury, Thomas

doi:10.1002/jcph.848

Cited by 13 publications

(14 citation statements)

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“…The PI3K inhibitor (PI3Ki) buparlisib (BKM120) and the MEK inhibitor (MEKi) selumetinib (AZD6244) were purchased from MedChem Express (Monmouth Junction, NJ) or Chemietek (Indianapolis, IN) and dissolved in dimethyl sulfoxide (DMSO). In single-dose pharmacokinetics studies in human patients, maximum observed plasma concentrations for buparlisib and selumetinib were 2–5 μM (1–2 μg/mL) and 1.1–2.0 μM (0.5–0.9 μg/mL), respectively [ 39 , 40 ]. Depending on experimental requirements, drugs were used at or above these clinically relevant dose ranges.…”

Section: Methodsmentioning

confidence: 99%

PIK3CA missense mutations promote glioblastoma pathogenesis, but do not enhance targeted PI3K inhibition

et al. 2018

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BackgroundGlioblastoma (GBM) is the most common adult primary brain tumor. Multimodal treatment is empiric and prognosis remains poor. Recurrent PIK3CA missense mutations (PIK3CAmut) in GBM are restricted to three functional domains: adaptor binding (ABD), helical, and kinase. Defining how these mutations influence gliomagenesis and response to kinase inhibitors may aid in the clinical development of novel targeted therapies in biomarker-stratified patients.MethodsWe used normal human astrocytes immortalized via expression of hTERT, E6, and E7 (NHA). We selected two PIK3CAmut from each of 3 mutated domains and induced their expression in NHA with (NHARAS) and without mutant RAS using lentiviral vectors. We then examined the role of PIK3CAmut in gliomagenesis in vitro and in mice, as well as response to targeted PI3K (PI3Ki) and MEK (MEKi) inhibitors in vitro.ResultsPIK3CAmut, particularly helical and kinase domain mutations, potentiated proximal PI3K signaling and migration of NHA and NHARAS in vitro. Only kinase domain mutations promoted NHA colony formation, but both helical and kinase domain mutations promoted NHARAS tumorigenesis in vivo. PIK3CAmut status had minimal effects on PI3Ki and MEKi efficacy. However, PI3Ki/MEKi synergism was pronounced in NHA and NHARAS harboring ABD or helical mutations.ConclusionPIK3CAmut promoted differential gliomagenesis based on the mutated domain. While PIK3CAmut did not influence sensitivity to single agent PI3Ki, they did alter PI3Ki/MEKi synergism. Taken together, our results demonstrate that a subset of PIK3CAmut promote tumorigenesis and suggest that patients with helical domain mutations may be most sensitive to dual PI3Ki/MEKi treatment.

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Section: Methodsmentioning

confidence: 99%

PIK3CA missense mutations promote glioblastoma pathogenesis, but do not enhance targeted PI3K inhibition

et al. 2018

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“…The pharmacokinetics (PK) of selumetinib have been evaluated both in healthy subjects and patients with various tumours . Approximately dose‐proportional PK were observed for selumetinib doses up to 100 mg twice daily , and 75 mg twice daily was established as the maximum tolerated dose for selumetinib .…”

Section: Introductionmentioning

confidence: 99%

“…Selumetinib drug–drug interactions (DDIs), bioavailability, food effects, and hepatic and renal impairment effects have been evaluated in multiple clinical pharmacology studies . The objectives of the current analysis were to develop a population PK model of selumetinib and its N‐desmethyl metabolite in healthy subjects, following oral and IV administration of selumetinib, and to evaluate the influence of covariates on the population PK parameters of selumetinib and N‐desmethyl selumetinib.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of the MEK inhibitor selumetinib and its active N‐desmethyl metabolite: data from 10 phase I trials

Patel¹,

Howgate²,

Martín

et al. 2017

Brit J Clinical Pharma

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AIMSThe aims of the study were to characterize the pharmacokinetics (PK) of selumetinib (AZD6244; ARRY-142886), a mitogenactivated protein kinase kinase (MEK) 1/2 inhibitor in clinical development for various indications, and its N-desmethyl metabolite in healthy volunteers, and evaluate clinically important covariates. METHODSA pooled-population PK analysis was performed using a nonlinear mixed-effects approach with plasma concentration data from 346 subjects who received single oral doses of selumetinib 20-75 mg across 10 phase I studies. Absolute bioavailability was determined using intravenous [ 14 C] selumetinib. RESULTSA two-compartment linear model with sequential zero-first order absorption and a lag time for the zero-order process was described for selumetinib PK. N-desmethyl metabolite disposition was described by a single compartment with linear elimination, without back transformation. The parent-only and joint models generally described pooled data adequately. For the median subject, not taking interacting drugs, estimates for clearance (CL) and central volume of distribution (V2) for selumetinib in the final joint model were 12.7 l h -1 and 35.6 l, respectively. Food effects, comedication with itraconazole [a cytochrome P450 (CYP) 3A4 inhibitor], fluconazole (a CYP2C19 inhibitor) and rifampicin (a CYP3A4 inducer) and formulation effects were incorporated into the base model a priori. Race and hepatic function were also influential in the PK model. Additional covariates affecting selumetinib disposition identified from covariate analysis were age on V2, bilirubin on CL, and weight on CL and V2. CONCLUSIONSAnalysis confirmed previous clinical pharmacology study findings of drug-drug interactions and food effects, with additional covariates that influence selumetinib and N-desmethyl selumetinib PK identified. Dose modifications based on these additional covariates were not considered necessary. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Drug-drug interactions, bioavailability, food effects and hepatic/renal impairment effects of selumetinib have previously been evaluated in numerous clinical studies in healthy subjects. Our aim was to develop a population pharmacokinetic (PK) model of selumetinib and its N-desmethyl metabolite in healthy subjects, and to identify important covariates influencing the PK. WHAT THIS STUDY ADDS• We confirmed that food effects, comedication with cytochrome P450 inhibitors/inducers, race and hepatic function status were influential in the PK model, as indicated by previous studies. We identified additional covariates, including age, bilirubin level and weight, that influence selumetinib and N-desmethyl selumetinib PK.

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“…Additional safety and tolerability data for the Western studies are reported in detail elsewhere and include references [20–22]. …”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and pharmacogenetics of the MEK1/2 inhibitor, selumetinib, in Asian and Western healthy subjects: a pooled analysis

Dymond

Elks

Martín

et al. 2017

Eur J Clin Pharmacol

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PurposeEmerging data on selumetinib, a MEK1/2 inhibitor in clinical development, suggest a possible difference in pharmacokinetics (PK) between Japanese and Western patients. This pooled analysis sought to assess the effect of ethnicity on selumetinib exposure in healthy Western and Asian subjects, and to identify any association between genetic variants in the UGT1A1, CYP2C19 and ABCG2 genes and observed differences in selumetinib PK.MethodsA pooled analysis of data from ten Phase I studies, one in Asian subjects (encompassing Japanese, non-Japanese Asian and Indian Asian subjects) and nine in Western subjects, was conducted. Key findings were derived from the collective exposure data across doses of 25, 35, 50 and 75 mg selumetinib; primary variables were dose-normalized AUC and Cmax.ResultsPK data from 308 subjects (10 studies) were available for the pooled analysis; genetic data from 87 subjects (3 studies) were available for the pharmacogenetic analysis. Dose-normalized AUC and Cmax were 35% (95% CI: 25–47%) and 39% (95% CI: 24–56%) higher in the pooled Asian group, respectively, compared with Western subjects. PK exposure parameters were similar between the Japanese, non-Japanese Asian and Indian groups. There was no evidence that the polymorphisms assessed in the genes UGT1A1, CYP2C19 and ABCG2 account for observed PK differences.ConclusionsSelumetinib exposure was higher in healthy Asian subjects compared with Western subjects, and these data provide valuable insight for clinicians to consider when treating patients of Asian ethnicity with selumetinib.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-017-2217-3) contains supplementary material, which is available to authorized users.

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Pharmacokinetics of a Single Oral Dose of the MEK1/2 Inhibitor Selumetinib in Subjects With End‐Stage Renal Disease or Varying Degrees of Hepatic Impairment Compared With Healthy Subjects

Cited by 13 publications

References 10 publications

PIK3CA missense mutations promote glioblastoma pathogenesis, but do not enhance targeted PI3K inhibition

PIK3CA missense mutations promote glioblastoma pathogenesis, but do not enhance targeted PI3K inhibition

Population pharmacokinetics of the MEK inhibitor selumetinib and its active N‐desmethyl metabolite: data from 10 phase I trials

Pharmacokinetics and pharmacogenetics of the MEK1/2 inhibitor, selumetinib, in Asian and Western healthy subjects: a pooled analysis

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