Eechoute, K.

Long-term prospective population PK study in GIST patients - Response (Article)

2013-02-15T00:00:00Z

Polymorphisms in endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) predict sunitinib-induced hypertension (Article)

2012-10-01T00:00:00Z

Hypertension is an important side effect of sunitinib treatment. In a retrospective study in 255 patients, single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor (VEGFR)-2, endothelin-1 (ET-1), and endothelium-derived nitric oxide synthase (eNOS) were multivariately tested against hypertension grades and changes in systolic blood pressure (SBP), diastolic BP (DBP), and mean arterial BP (MAP). Next, the association between hypertension and survival in patients with metastatic renal cell cancer (mRCC) was studied. Greater elevations in SBP and MAP were associated with the presence of a haplotype in VEGFA (P = 0.014 and P = 0.036, respectively). The tendency to develop grade 3 hypertension was associated with this haplotype and also with a SNP in eNOS (P = 0.031 and P = 0.045, respectively). In mRCC patients, sunitinib-induced hypertension was found to confer a survival benefit, with the mean overall survival being prolonged by 7.2 months (P = 0.035 and P = 0.026 for SBP and DBP elevations, respectively). Genetic polymorphisms in VEGFA and eNOS independently predict rise in BP and/or development of severe hypertension in sunitinib-treated patients. Grade 3 hypertension was found to be an independent factor for overall survival in patients with mRCC.

Towards a pharmacologically guided individualization of imatinib and sunitnib therapy (Doctoral Thesis)

2012-04-25T00:00:00Z

The approval of imatinib mesylate (Gleevec™) in 2001 has added a new class of drugs to the systemic treatment of cancer: that of the tyrosine kinase inhibitors (TKIs). Imatinib inhibits autophosphorylation of specific proteins involved in oncogenesis such as the BCR-ABL fusion protein (expressed in Philadelphia chromosome positive chronic myeloid leukemia), c-KIT (expressed in gastrointestinal stromal tumors; GIST) and the plateletderived growth factor receptor (PDGFR; i.e. expressed in GIST and several sarcomas). After a decade of therapeutic use, imatinib has proven to be a highly effective targeted agent with a median overall survival in advanced GIST patients close to 5 years.

Towards a pharmacologically guided individualization of imatinib and sunitnib therapy (Doctoral Thesis)

2012-04-25T00:00:00Z

The approval of imatinib mesylate (Gleeve) in 2001 has added a new class of drugs to the systemic treatment of cancer: that of the tyrosine kinase inhibitors (TKIs). Imatinib inhibits autophosphorylation of specific proteins involved in oncogenesis such as the BCR-ABL fusion protein (expressed in Philadelphia chromosome positive chronic myeloid leukemia), c-KIT (expressed in gastrointestinal stromal tumors; GIST) and the plateletderived growth factor receptor (PDGFR; i.e. expressed in GIST and several sarcomas). After a decade of therapeutic use, imatinib has proven to be a highly effective targeted agent with a median overall survival in advanced GIST patients close to 5 years.

Sunitinib-induced hypothyroidism is due to induction of type 3 deiodinase activity and thyroidal capillary regression (Article)

2011-10-01T00:00:00Z

Context: Anticancer treatment with the tyrosine kinase inhibitor sunitinib causes thyroid dysfunction. Objective: Our objective was to investigate the time course and underlying mechanisms of sunitinib-induced thyroid dysfunction. Design: Thyroid function tests of 83 patients on sunitinib were collected retrospectively for their total treatment duration between January 2006 and November 2009 and prospectively in 15 patients on sunitinib for 10 wk. Additionally, thyroid function and histology were assessed in rats on sunitinib (8 d; n = 10) and after sunitinib withdrawal (11 d; n = 7) and compared with controls (n = 7). Setting: Patients were seen at a university outpatient oncology clinic. Patients and Animals: Patients with metastatic renal cell carcinoma or gastrointestinal stromal tumors participated in the clinical study and Wistar Kyoto rats were used in the rat study. Intervention: Sunitinib was taken according to a 4 wk "on," 2 wk "off" treatment regimen. Blood samples for measurement of thyroid function were collected at baseline and at wk 4 and 10. In rats, blood, liver, and thyroid were collected to assess thyroid hormones, deiodinase activity, and thyroid histology. Main Outcome Measures: TSH and free T4levels, deiodinase activity, and thyroid histology were assessed. Results: Forty-two percent of patients in the retrospective study developed elevated TSH levels. Prospective analysis showed increased TSH levels within 10 wk of treatment, accompanied by a decreased T3/rT3ratio. In rats, serum T4and T3decreased, hepatic type 3 deiodinase activity increased, andthyroid histology showed marked capillary regression, which all but thyroid hormones reversed after sunitinib withdrawal. Conclusion: Sunitinib induces hypothyroidism due to alterations in T4/T3metabolism as well as thyroid capillary regression. Copyright

Environmental and Genetic Factors Affecting Transport of Imatinib by OATP1A2 (Article)

2011-04-20T00:00:00Z

The bioavailability of orally administered imatinib is >90%, although the drug is monocationic under the acidic conditions in the duodenum. In vitro, we found that imatinib is transported by the intestinal uptake carrier organic anion transporting polypeptide (OATP1A2) and that this process is sensitive to pH, rosuvastatin, and genetic variants. However, in a study in patients with cancer, imatinib absorption was not associated with OATP1A2 variants and was unaffected by rosuvastatin. These findings highlight the importance of verifying in a clinical setting the drug-transporter interactions observed in in vitro tests.

Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib (Article)

2011-02-01T00:00:00Z

Purpose: The objective of this study was to identify genetic polymorphisms related to the pharmacokinetics and pharmacodynamics of sunitinib that are associated with a prolonged progression-free survival (PFS) and/or overall survival (OS) in patients with clear-cell metastatic renal cell cancer (mRCC) treated with sunitinib. Experimental design: A retrospective multicenter pharmacogenetic association study was performed in 136 clear-cell mRCC patients treated with sunitinib. A total of 30 polymorphisms in 11 candidate genes, together with clinical characteristics were tested univariately for association with PFS as primary and OS as secondary outcome. Candidate variables with P < 0.1 were analyzed in a multivariate Cox regression model. Results: Multivariate analysis showed that PFS was significantly improved when an A-allele was present in CYP3A5 6986A/G [hazard ratio (HR), 0.27; P = 0.032], a CAT copy was absent in the NR1I3 haplotype (5719C/T, 7738A/C, 7837T/G; HR, 1.76; P = 0.017) and a TCG copy was present in the ABCB1 haplotype (3435C/T, 1236C/T, 2677G/T; HR, 0.52; P = 0.033). Carriers with a favorable genetic profile (n = 95) had an improved PFS and OS as compared with noncarriers (median PFS and OS: 13.1 versus 7.5 months and 19.9 versus 12.3 months). Next to the genetic variants, the Memorial Sloan-Kettering Cancer Center prognostic criteria were associated with PFS and OS (HR, 1.99 and 2.27; P < 0.001). Conclusions: This exploratory study shows that genetic polymorphisms in three genes involved in sunitinib pharmacokinetics are associated with PFS in mRCC patients treated with this drug. These findings advocate prospective validation and further elucidation of these genetic determinants in relation to sunitinib exposure and efficacy.

Drug transporters and imatinib treatment: Implications for clinical practice (Article)

2011-02-01T00:00:00Z

Imatinib mesylate is approved for the treatment of chronic myeloid leukemia (CML) and advanced gastrointestinal stromal tumors (GIST). Unfortunately, in the course of treatment, disease progression occurs in the majority of patients with GIST. Lowered plasma trough levels of imatinib over time potentially cause disease progression, a phenomenon known as "acquired pharmacokinetic drug resistance." This outcome may be the result of an altered expression pattern or activity of drug transporters. To date, the role of both efflux transporters (ATP-binding cassette transporters, such as ABCB1 and ABCG2) and uptake transporters [solute carriers such as organic cation transporter 1 (OCT1) and organic anion transporting polypeptide 1A2 (OATP1A2)] in imatinib pharmacokinetics and pharmacodynamics has been studied. In vitro experiments show a significant role of ABCB1 and ABCG2 in cellular uptake and retention of imatinib, although pharmacokinetic and pharmacogenetic data are still scarce and contradictory. ABCB1 and ABCC1 expression was shown in GIST, whereas ABCB1, ABCG2, and OCT1 were found in mononuclear cells in CML patients. Several studies have reported a clinical relevance of tumor expression or activity of OCT1 in CML patients. Further (clinical) studies are required to quantify drug transporter expression over time in organs involved in imatinib metabolism, as well as in tumor tissue. In addition, more pharmacogenetic studies will be needed to validate associations.

Drug transporters of platinum-based anticancer agents and their clinical significance (Article)

2011-02-01T00:00:00Z

Platinum-based drugs are among the most active anticancer agents and are successfully used in a wide variety of human malignancies. However, acquired and/or intrinsic resistance still represent a major limitation. Lately, in particular mechanisms leading to impaired uptake and/or decreased cellular accumulation of platinum compounds have attracted attention. In this review, we focus on the role of active platinum uptake and efflux systems as determinants of platinum sensitivity and -resistance and their contribution to platinum pharmacokinetics (PK) and pharmacodynamics (PD). First, the three mostly used platinum-based anticancer agents as well as the most promising novel platinum compounds in development are put into clinical perspective. Next, we describe the presently known potential platinum transporters - with special emphasis on organic cation transporters (OCTs) - and discuss their role on clinical outcome (i.e. efficacy and adverse events) of platinum-based chemotherapy. In addition, transporter-mediated tumour resistance, the impact of potential platinum transporter-mediated drug-drug interactions, and the role of drug transporters in the renal elimination of platinum compounds are discussed.

Myelosuppression by sunitinib is flt-3 genotype dependent (Article)

2010-08-01T00:00:00Z