Population Pharmacokinetic and Exposure‐Response Analysis of Selumetinib and Its N‐desmethyl Metabolite in Patients With Non‐Small Cell Lung Cancer

Tong, Xiao; Xu, Hongmei; Carlile, David; Tomkinson, Helen; Al‐Huniti, Nidal; Zhou, Diansong

doi:10.1002/jcph.1295

Cited by 7 publications

(4 citation statements)

References 33 publications

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“…This dosing schedule required 6 hours of fasting per day, which could be inconvenient, especially in children. The pharmacokinetic (PK) parameters of selumetinib and its active metabolite N‐desmethyl selumetinib have been well characterized, including in healthy volunteers, patients with hepatic impairment, alone or in combination with chemotherapy in patients with advanced solid tumors, in combination with cytochrome P450 (CYP) enzyme‐modulating agents, and in adult or pediatric patients 9,14–19 . N‐desmethyl selumetinib is 3‐5 times more potent than selumetinib but has been found to account for only 10% of the circulating radioactivity in human plasma 2 hours after administration of 14 C‐selumetinib in healthy adults 12,19–22 .…”

Section: Figurementioning

confidence: 99%

A Population Pharmacokinetic Assessment of the Effect of Food on Selumetinib in Patients with Neurofibromatosis Type 1‐Related Plexiform Neurofibromas and Healthy Volunteers

Zuo,

Arefayene,

Pan

et al. 2024

Clinical Pharm in Drug Dev

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Selumetinib is clinically used for pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas. Until recently, selumetinib had to be taken twice daily, after 2 hours of fasting and followed by 1 hour of fasting, which could be inconvenient. This population analysis evaluated the effect of low‐ and high‐fat meals on the pharmacokinetic (PK) parameters of selumetinib and its active metabolite N‐desmethyl selumetinib. The dataset comprised 511 subjects from 15 clinical trials who received ≥1 dose of selumetinib and provided ≥1 measurable postdose concentration of selumetinib and N‐desmethyl selumetinib. A 2‐compartment model with sequential 0‐ and 1st‐order delayed absorption and 1st‐order elimination adequately described selumetinib PK characteristics. A 1‐compartment model reasonably described N‐desmethyl selumetinib PK characteristics over time simultaneously with selumetinib. Selumetinib geometric mean area under the concentration–time curve ratio (1‐sided 90% confidence interval [CI] lower bound) was 76.9% (73.3%) with a low‐fat meal and 79.3% (76.3%) with a high‐fat meal versus fasting. The lower bound of the 1‐sided 90% CI demonstrated a difference of <30% between fed and fasted states. Considering the flat exposure‐response relationship within the dose range (20‐30 mg/m2), the observed range of exposure, and the variability in the SPRINT trial, this was not considered clinically relevant.

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Section: Figurementioning

confidence: 99%

A Population Pharmacokinetic Assessment of the Effect of Food on Selumetinib in Patients with Neurofibromatosis Type 1‐Related Plexiform Neurofibromas and Healthy Volunteers

Zuo,

Arefayene,

Pan

et al. 2024

Clinical Pharm in Drug Dev

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“…A two-compartment model with first-order elimination was superior to a one-compartment model to describe yimitasvir PK profile. For the tested absorption model including first-order absorption with or without a lag time, sequential zero-first order absorption (Tong et al, 2018a;Tong et al, 2018b), transit absorption (Jain et al, 2011;Hu et al, 2018) and saturable Michaelis-Menten absorption (Wu et al, 2012), transit absorption model had the smallest AIC value and fitted the data best from the goodness-of-fit plots. Sequential zero-first order absorption model also performed well.…”

Section: Model Developmentmentioning

confidence: 99%

Population Pharmacokinetic Analysis of Yimitasvir in Chinese Healthy Volunteers and Patients With Chronic Hepatitis C Virus Infection

Guan

Tang

Zhang³

et al. 2021

Front. Pharmacol.

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Yimitasvir is a novel, oral hepatitis C virus (HCV) non-structural protein 5A inhibitor for the treatment of chronic HCV genotype 1 infection. The objective of this analysis was to develop a population pharmacokinetic model of yimitasvir in Chinese healthy volunteers and HCV infection patients. The model was performed using data from 219 subjects across six studies. Nonlinear mixed effects models were developed using Phoenix NLME software. The covariates were evaluated using a stepwise forward inclusion (p < 0.01) and then a backward exclusion procedure (p < 0.001). A two-compartment model with sequential zero-first order absorption and first-order elimination reasonably described yimitasvir pharmacokinetics (PK). The apparent oral clearance and central volume of distribution were 13.8 l·h−1 and 188 l, respectively. The bioavailability (F) of yimitasvir decreased 12.9% for each 100 mg dose increase. Food was found to affect absorption rate (Ka) and F. High-fat meal decreased Ka and F by 90.9% and 38.5%, respectively. Gender and alanine aminotransferase were identified as significant covariates on apparent oral clearance. Female subjects had lower clearance than male subjects. Zero-order absorption duration was longer in healthy volunteers (2.17 h) than that in patients (1.43 h). The population pharmacokinetic model described yimitasvir PK profile well. Food decreased Ka and F significantly, so it was recommended to take yimitasvir at least 2 h before or after a meal. Other significant covariates were not clinically important.

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“…Te pharmacokinetic (PK) profle of selumetinib, along with its active metabolite N-desmethyl selumetinib (3-5 times more potent than selumetinib, circulating at about 7% of selumetinib concentration in plasma, consequently about 20-30% contribution to the selumetinib activity), has been well characterized in several population pharmacokinetic (PopPK) analyses [15][16][17][18]. Te PK profles of selumetinib and N-desmethyl selumetinib are comparable among healthy subjects, adult patients with various tumors, and pediatric patients with NF1 and PN.…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetic Analysis of Selumetinib and Its N-desmethyl Metabolite in Japanese and Non-Japanese Pediatric Patients with Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas

Shinbo,

Higashimori,

González-García

et al. 2024

Journal of Clinical Pharmacy and Therapeutics

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Background. Selumetinib, a mitogen-activated protein kinase kinase 1/2 inhibitor, has been approved in several countries and regions, including Japan, for the treatment of pediatric patients with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas at a body surface area (BSA)-based dose of 25 mg/m2 twice daily. The objective of this population pharmacokinetic analysis was to evaluate ethnic sensitivity in the pharmacokinetics of selumetinib and N-desmethyl selumetinib between Japanese and non-Japanese pediatric patients. Methods. This population pharmacokinetic analysis was based on data from 80 pediatric patients enrolled in two clinical trials, one conducted in Japan and one conducted in the United States, comprising 12 Japanese participants and 68 non-Japanese participants. Both clinical trials used BSA-based dosing schemes. A two-compartment model with first-order elimination and sequential zero-order and first-order delayed absorption for selumetinib, combined with a one-compartment model with first-order elimination for N-desmethyl selumetinib, was used for this analysis. Ethnic sensitivity in pharmacokinetics was evaluated by covariate modeling and comparison of model-predicted exposures. Results. Covariate modeling showed that BSA had a clinically relevant impact on the pharmacokinetics of selumetinib. None of the other investigated covariates, such as race, had a significant impact. The predicted exposure in Japanese and non-Japanese patients showed a considerably overlapping distribution, and no clinically relevant difference in exposure was apparent. Conclusions. These findings support the use of the same BSA-based dosing regimen for Japanese and non-Japanese pediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas. Subsequent to this analysis, selumetinib was approved at the BSA-based dose of 25 mg/m2 in Japan, which is consistent with the recommended dosage and administration in other regions and countries. This analysis used data from trial registered with NCT04495127, and NCT01362803.

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Population Pharmacokinetic and Exposure‐Response Analysis of Selumetinib and Its N‐desmethyl Metabolite in Patients With Non‐Small Cell Lung Cancer

Cited by 7 publications

References 33 publications

A Population Pharmacokinetic Assessment of the Effect of Food on Selumetinib in Patients with Neurofibromatosis Type 1‐Related Plexiform Neurofibromas and Healthy Volunteers

A Population Pharmacokinetic Assessment of the Effect of Food on Selumetinib in Patients with Neurofibromatosis Type 1‐Related Plexiform Neurofibromas and Healthy Volunteers

Population Pharmacokinetic Analysis of Yimitasvir in Chinese Healthy Volunteers and Patients With Chronic Hepatitis C Virus Infection

Population Pharmacokinetic Analysis of Selumetinib and Its N-desmethyl Metabolite in Japanese and Non-Japanese Pediatric Patients with Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas

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