BSA and ABCB1 polymorphism affect the pharmacokinetics of sunitinib and its active metabolite in Asian mRCC patients receiving an attenuated sunitinib dosing regimen

Chae, Jung-Woo; Teo, Yi Ling; Ho, Han Kiat; Lee, Jaeyeon; Back, Hyun-moon; Yun, Hyo-In; Karlsson, Mats O.; Kwon, Kwang‐il; Chan, Alexandre

doi:10.1007/s00280-016-3104-9

Cited by 9 publications

(9 citation statements)

References 40 publications

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“…10,11,37,39–44 Other factors such as cigarette smoking, gender, body weight, and age have also been associated with sunitinib toxicity and treatment outcomes. 33,42,43,45–47 Individualization of sunitinib treatment based on genetic and nongenetic factors has been proposed to help improve sunitinib efficacy and reduce toxicity. 10,48,49 …”

Section: Discussionmentioning

confidence: 99%

Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib

Amaya

Durandis

Bourgeois

et al. 2018

Chem. Res. Toxicol.

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Sunitinib is a multitargeted tyrosine kinase inhibitor associated with idiosyncratic hepatotoxicity. The mechanisms of this toxicity are unknown. We hypothesized that sunitinib undergoes metabolic activation to form chemically reactive, potentially toxic metabolites which may contribute to development of sunitinib-induced hepatotoxicity. The purpose of this study was to define the role of cytochrome P450 (P450) enzymes in sunitinib bioactivation. Metabolic incubations were performed using individual recombinant P450s, human liver microsomal fractions, and P450-selective chemical inhibitors. Glutathione (GSH) and dansylated GSH were used as trapping agents to detect reactive metabolite formation. Sunitinib metabolites were analyzed by liquid chromatography–tandem mass spectrometry. A putative quinoneimine–GSH conjugate (M5) of sunitinib was detected from trapping studies with GSH and dansyl–GSH in human liver microsomal incubations, and M5 was formed in an NADPH-dependent manner. Recombinant P450 1A2 generated the highest levels of defluorinated sunitinib (M3) and M5, with less formation by P450 3A4 and 2D6. P450 3A4 was the major enzyme forming the primary active metabolite N-desethylsunitinib (M1). In human liver microsomal incubations, P450 3A inhibitor ketoconazole reduced formation of M1 by 88%, while P450 1A2 inhibitor furafylline decreased generation of M5 by 62% compared to control levels. P450 2D6 and P450 3A inhibition also decreased M5 by 54 and 52%, respectively, compared to control. In kinetic assays, recombinant P450 1A2 showed greater efficiency for generation of M3 and M5 compared to that of P450 3A4 and 2D6. Moreover, M5 formation was 2.7-fold more efficient in human liver microsomal preparations from an individual donor with high P450 1A2 activity compared to a donor with low P450 1A2 activity. Collectively, these data suggest that P450 1A2 and 3A4 contribute to oxidative defluorination of sunitinib to generate a reactive, potentially toxic quinoneimine. Factors that alter P450 1A2 and 3A activity may affect patient risk for sunitinib toxicity.

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Section: Discussionmentioning

confidence: 99%

Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib

Amaya

Durandis

Bourgeois

et al. 2018

Chem. Res. Toxicol.

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“…For sunitinib, several population PK models have been developed . The PK of sunitinib and SU012662 is described as a one‐ or two‐compartment model with first‐order absorption and elimination.…”

Section: Methodsmentioning

confidence: 99%

“…For sunitinib, several population PK models have been developed. 96,[113][114][115][116][117][118][119][120] The PK of sunitinib and SU012662 is described as a one-or two-compartment model with first-order absorption and elimination. Some covariates might explain part of the interpatient PK variability.…”

Section: Factors Identified In Pharmacokinetic Models That Explain Inmentioning

confidence: 99%

“…Several studies have shown that sunitinib clearance decreases with decreasing body weight, body surface area and lean body mass. 113,117,119 Also, increasing age causes a slight decrease in sunitinib clearance of 0.7% per year. 116 Finally, sunitinib clearance is decreased in women compared to men.…”

Section: Factors Identified In Pharmacokinetic Models That Explain Inmentioning

confidence: 99%

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Imatinib, sunitinib and pazopanib: From flat‐fixed dosing towards a pharmacokinetically guided personalized dose

Westerdijk¹,

Desar²,

Steeghs

et al. 2020

Brit J Clinical Pharma

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Tyrosine kinase inhibitors (TKIs) are anti‐cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral TKIs have been introduced in the treatment of solid tumours, all administered in a fixed dose, although large interpatient pharmacokinetic (PK) variability is described. For imatinib, sunitinib and pazopanib exposure‐treatment outcome (efficacy and toxicity) relationships have been established and therapeutic windows have been defined, therefore dose optimization based on the measured blood concentration, called therapeutic drug monitoring (TDM), can be valuable in increasing efficacy and reducing the toxicity of these drugs. In this review, an overview of the current knowledge on TDM guided individualized dosing of imatinib, sunitinib and pazopanib for the treatment of solid tumours is presented. We summarize preclinical and clinical data that have defined thresholds for efficacy and toxicity. Furthermore, PK models and factors that influence the PK of these drugs which partly explain the interpatient PK variability are summarized. Finally, pharmacological interventions that have been performed to optimize plasma concentrations are described. Based on current literature, we advise which methods should be used to optimize exposure to imatinib, sunitinib and pazopanib.

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“…63 SU is similar to IM, and the clearance rate of SU decreases with the decrease of body weight and BSA. 64,65 Women have lower apparent clearance than men, but even if there is such a difference, there is no evidence that women's doses need to be adjusted. 66 With the increase of age, the clearance rate of SU decreased slightly by about 0.7%.…”

Section: Metabolic Related Factorsmentioning

confidence: 99%

Individualized Management of Blood Concentration in Patients with Gastrointestinal Stromal Tumors

Xu¹,

Liu²

2021

OTT

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BSA and ABCB1 polymorphism affect the pharmacokinetics of sunitinib and its active metabolite in Asian mRCC patients receiving an attenuated sunitinib dosing regimen

Abstract: Adjusting doses of sunitinib according to BSA and ABCB1 polymorphism in Asian mRCC patients may be recommended for sufficient attainment of a target TTL of sunitinib and its metabolite.

Cited by 9 publications

References 40 publications

Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib

Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib

Imatinib, sunitinib and pazopanib: From flat‐fixed dosing towards a pharmacokinetically guided personalized dose

Individualized Management of Blood Concentration in Patients with Gastrointestinal Stromal Tumors

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