ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Indoles/pharmacology , Indoles/pharmacokinetics , Models, Biological , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Pyrroles/pharmacology , Pyrroles/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B/genetics , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/blood , Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/blood , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/genetics , Colorectal Neoplasms/blood , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Cytochrome P-450 CYP3A/genetics , Female , Genotype , Humans , Indoles/blood , Indoles/therapeutic use , Interleukin-8/genetics , Kidney Neoplasms/blood , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , Male , Middle Aged , Polymorphism, Single Nucleotide , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/therapeutic use , Pyrroles/blood , Pyrroles/therapeutic use , Sunitinib , Treatment Outcome , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor Receptor-2/blood , Vascular Endothelial Growth Factor Receptor-2/genetics , Vascular Endothelial Growth Factor Receptor-3/blood , Vascular Endothelial Growth Factor Receptor-3/geneticsABSTRACT
The single nucleotide polymorphism (SNP) rs4646437G>A in CYP3A4 was suggested to be related to sunitinib toxicity. Our objective was to perform an in-depth investigation of the association between this SNP and sunitinib toxicity and efficacy using a large cohort of metastatic renal cell carcinoma (mRCC) patients. We collected DNA and clinical information of mRCC patients treated with sunitinib. SNP rs4646437 in CYP3A4 was tested for associations with toxicity using logistic regression. Cox regression modeling was used for association analysis of rs4646437 with progression-free survival (PFS) and overall survival (OS). In a total of 287 patients, the A-allele of CYP3A4 rs4646437 was associated with an increased risk for hypertension (odds ratio=2.4, 95% confidence interval: 1.1-5.2, P=0.021) and showed no significant association with PFS or OS. In conclusion, hypertension is more likely to occur in A-allele carriers of the CYP3A4 rs4646437 variant in our cohort of mRCC patients treated with sunitinib.
Subject(s)
Angiogenesis Inhibitors/adverse effects , Carcinoma, Renal Cell/drug therapy , Cytochrome P-450 CYP3A/genetics , Hypertension/genetics , Indoles/adverse effects , Kidney Neoplasms/drug therapy , Pharmacogenomic Variants , Polymorphism, Single Nucleotide , Protein Kinase Inhibitors/adverse effects , Pyrroles/adverse effects , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/enzymology , Carcinoma, Renal Cell/secondary , Chi-Square Distribution , Cytochrome P-450 CYP3A/metabolism , Disease-Free Survival , Europe , Female , Gene Frequency , Genetic Predisposition to Disease , Heterozygote , Homozygote , Humans , Hypertension/chemically induced , Hypertension/enzymology , Kidney Neoplasms/enzymology , Kidney Neoplasms/pathology , Logistic Models , Male , Middle Aged , Multivariate Analysis , Odds Ratio , Ohio , Phenotype , Proportional Hazards Models , Retrospective Studies , Risk Factors , Sunitinib , Time Factors , Treatment OutcomeABSTRACT
Interpatient variability in the pharmacokinetics (PK) of sunitinib is high. Single nucleotide polymorphisms (SNPs) in PK candidate genes have been associated with the efficacy and toxicity of sunitinib, but whether these SNPs truly affect the PK of sunitinib remains to be elucidated. This multicenter study involving 114 patients investigated whether these SNPs and haplotypes in genes encoding metabolizing enzymes or efflux transporters are associated with the clearance of sunitinib and its active metabolite SU12662. SNPs were tested as covariates in a population PK model. From univariate analysis, we found that the SNPs in CYP3A4, CYP3A5, and ABCB1 were associated with the clearance of both sunitinib and SU12662. In multivariate analysis, CYP3A4*22 was found to be eliminated last with an effect size of -22.5% on clearance. Observed effect sizes are below the interindividual variability in clearance and are therefore too limited to directly guide individual dosing of sunitinib.
