Efflux pump ABCB1 single nucleotide polymorphisms and dose reductions in patients with metastatic renal cell carcinoma treated with sunitinib

Beuselinck, Benoît; Lambrechts, Diether; Brussel, Thomas Van; Wolter, Pascal; Cardinaels, Nina; Joniau, Steven; Lerut, Evelyne; Karadimou, Alexandra; Couchy, Gabrielle; Sèbe, Philippe; Ravaud, Alain; Zerbib, Marc; Caty, Armelle; Paridaens, Robert; Schöffski, Patrick; Verkarre, Virginie; Berger, J.; Patard, Jean‐Jacques; Zucman‐Rossi, Jessica; Oudard, Stéphane

doi:10.3109/0284186x.2014.918276

Cited by 31 publications

(26 citation statements)

References 20 publications

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“…On PK, the results show that SNPs in genes coding for CYP enzymes, CYP regulators, and drug efflux transporters (ABCB1, ABCC2, and ABCG2) seem to play an important role in sunitinib treatment outcome, especially CYP3A5 and ABCB1 SNPs [19][20][21]29,31,34,37]. In some of the articles on sunitinib, the intermediate endpoints clearance and exposure were investigated and confirmed the hypotheses that SNPs in CYP3A4, CYP3A5, and ABCB1 influence drug exposure [22,29,36,37] (Figure 2).…”

Section: Discussionmentioning

confidence: 86%

See 1 more Smart Citation

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

Diekstra

Swen

Gelderblom

et al. 2016

Expert Review of Molecular Diagnostics

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Section: Discussionmentioning

confidence: 86%

“…In a study of Beuselinck et al, an increased time-to-dose reduction was seen for the TT genotype patients of rs1128503 and rs2032582 in ABCB1 compared to C-allele and G-allele carriers, respectively [21].…”

Section: Pharmacogenetics To Predict Sunitinib Toxicitymentioning

confidence: 99%

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

Diekstra

Swen

Gelderblom

et al. 2016

Expert Review of Molecular Diagnostics

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“…In 19 Japanese patients with renal carcinoma, the C1236T, G2677T/A and C3435T polymorphisms had no effect on kinetics [136]. One study of 88 mainly Caucasian renal cancer patients showed an association of the 1236TT genotype with lower overall and progression-free survival rates [137], and a subsequent analysis reported less need for dose reductions due to adverse effects [138]. However, a multicentre, observational, prospective study including 101 patients with advanced renal cell carcinoma treated with first-line sunitinib did not show any significant influence of the ABCB1 genotype [139].…”

Section: Sunitinibmentioning

confidence: 94%

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

et al. 2015

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ATP-binding cassette transporter B1 (ABCB1; P-glycoprotein; multidrug resistance protein 1) is an adenosine triphosphate (ATP)-dependent efflux transporter located in the plasma membrane of many different cell types. Numerous structurally unrelated compounds, including drugs and environmental toxins, have been identified as substrates. ABCB1 limits the absorption of xenobiotics from the gut lumen, protects sensitive tissues (e.g. the brain, fetus and testes) from xenobiotics and is involved in biliary and renal secretion of its substrates. In recent years, a large number of polymorphisms of the ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1] gene have been described. The variants 1236C>T (rs1128503, p.G412G), 2677G>T/A (rs2032582, p.A893S/T) and 3435C>T (rs1045642, p.I1145I) occur at high allele frequencies and create a common haplotype; therefore, they have been most widely studied. This review provides an overview of clinical studies published between 2002 and March 2015. In summary, the effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance. Future research activities are warranted, considering a deep-sequencing approach, as well as well-designed clinical studies with appropriate sample sizes to elucidate the impact of rare ABCB1 variants and their potential consequences for effect sizes.

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“…Herein, we have focused on SNPs that were very likely to have an effect on VEGF or VEGFRs, or SNPs that have a high biomarker potential because of confirmatory findings in large cohorts. Thirteen SNPs were selected located in CYP3A5, ABCB1, VEGF-A, VEGFR-2, VEGFR-3, and interleukin-8 [9][10][11][12][13][14][15][16][17][18][19][20][21][22] (details are provided in Supplementary Material S1).…”

Section: Snp Selection and Genotypingmentioning

confidence: 99%

“…8 With regard to genetic predictors, previous studies associated single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes or transporters related to pharmacokinetics (PKs) and pharmacodynamics (PDs) of sunitinib with efficacy and toxicity. [9][10][11][12][13][14][15][16][17][18][19][20][21][22] In order to find predictive biomarkers for the clinical outcome of sunitinib, a better understanding of the relationships between sunitinib exposure, the pharmacological response, and the clinical outcomes is vital. This is part of the objectives of the European collaborative project Euro-TARGET.…”

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confidence: 99%

Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients With Sunitinib‐Treated Cancer

Diekstra

Fritsch

Kanefendt

et al. 2017

CPT Pharmacom & Syst Pharma

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The tyrosine kinase inhibitor sunitinib is used as first‐line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed‐dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR‐2 and sVEGFR‐3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C‐II‐005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time‐to‐event (TTE) models. Baseline sVEGFR‐2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD‐guided strategies for the individualization of anti‐angiogenic therapies.

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Efflux pump ABCB1 single nucleotide polymorphisms and dose reductions in patients with metastatic renal cell carcinoma treated with sunitinib

Abstract: (2014) Efflux pump ABCB1 single nucleotide polymorphisms and dose reductions in patients with metastatic renal cell carcinoma treated with sunitinib,

Cited by 31 publications

References 20 publications

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients With Sunitinib‐Treated Cancer

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