Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability

Widmer, Nicolas; Décosterd, Laurent A.; Leyvraz, Serge; Duchosal, Michel A.; Rosselet, Anne; Dębiec‐Rychter, Maria; Csajka, Chantal; Biollaz, J; Buclin, Thierry

doi:10.1038/sj.bjc.6604355

Cited by 102 publications

(84 citation statements)

References 51 publications

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“…Although a majority of nonresponding patients harbor mutations in the molecular drug targets (3,7,8), early resistance may also result from imatinib plasma levels that are below a minimal effective threshold level. Although not significant, patients with GIST not responding to imatinib treatment have shown lower imatinib plasma levels than responders (9,10). In addition, in a retrospective pharmacokinetic sidestudy of the pivotal phase II B2222 trial, a significant shorter time to progression was observed in patients that showed one-month imatinib steady-state trough levels below 1,100 ng/mL (10).…”

Section: Introductionmentioning

confidence: 99%

A Long-term Prospective Population Pharmacokinetic Study on Imatinib Plasma Concentrations in GIST Patients

Eechoute

Fransson

Reyners

et al. 2012

Clinical Cancer Research

100

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Purpose: Imatinib minimal (trough) plasma concentrations after one month of treatment have shown a significant association with clinical benefit in patients with gastrointestinal stromal tumors (GIST). Considering that a retrospective pharmacokinetic analysis has also suggested that imatinib clearance increases over time in patients with soft tissue sarcoma and GIST, the primary aim of this study was to assess systemic exposure to imatinib at multiple time points in a long-term prospective population pharmacokinetic study. As imatinib is mainly metabolized in the liver, our secondary aim was to elucidate the potential effects of the volume of liver metastases on exposure to imatinib.Experimental Design: Full pharmacokinetic blood sampling was conducted in 50 patients with GIST on the first day of imatinib treatment, and after one, six, and 12 months. In addition, on day 14, and monthly during imatinib treatment, trough samples were taken. Pharmacokinetic analysis was conducted using a compartmental model. Volume of liver metastases was assessed by computed tomographic (CT) imaging.Results: After 90 days of treatment, a significant decrease in imatinib systemic exposure of 29.3% compared with baseline was observed (P < 0.01). For every 100 cm 3 increase of metastatic volume, a predicted decrease of 3.8% in imatinib clearance was observed.Conclusions: This is the first prospective pharmacokinetic study in patients with GIST, showing a significant decrease of approximately 30% in imatinib exposure after long-term treatment. This means that future "trough level -clinical benefit" analyses should be time point specific. GIST liver involvement, however, has a marginal effect on imatinib clearance.

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Section: Introductionmentioning

confidence: 99%

A Long-term Prospective Population Pharmacokinetic Study on Imatinib Plasma Concentrations in GIST Patients

Eechoute

Fransson

Reyners

et al. 2012

Clinical Cancer Research

100

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“…A recent PK-PD analysis by Widmer et al, 33 using data from 58 patients, did not determine a straightforward correlation between free imatinib plasma exposure and clinical response, but further experiments may be warranted to clarify the role of variability in a 1 -acid glycoprotein activity on imatinib response.…”

Section: Differential Binding Of Imatinib By a 1 -Acid Glycoproteinmentioning

confidence: 99%

“…Although there is evidence of a link between imatinib exposure and toxicity in CML, 33 the correlation between plasma imatinib concentrations and adverse events may not be linear. In the IRIS trial, some adverse events were seen more frequently in patients with intermediate or lower plasma concentrations.…”

Section: Unusually Severe Adverse Reactionsmentioning

confidence: 99%

Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia

et al. 2009

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“…Although there is evidence of a link between imatinib plasma concentration and adverse events (AEs), 29 the characteristics of any such correlation are largely unknown. An analysis of data from the IRIS trial showed no major differences between the types and grades of AEs reported in patients in each of the trough plasma imatinib concentration quartiles.…”

Section: What Is the Relationship Between Imatinib Levels And Adversementioning

confidence: 99%

Imatinib Blood Level Testing – Current Perspectives and Key Questions

Mahon¹,

Molimard²,

Foryciarz³

et al. 2010

European Oncology &Amp; Haematology

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Imatinib is the gold standard for the treatment of chronic myeloid leukaemia. Several recent studies have revealed a correlation between imatinib trough plasma levels and clinical response, suggesting that measurement of plasma levels can be a useful tool for optimising imatinib dose. However, a number of important questions on the use of imatinib blood level testing (BLT) remain unanswered. These questions were discussed at a European expert meeting held in Bordeaux, France, under the auspices of the European Treatment and Outcome Study (EUTOS) for chronic myeloid leukaemia. The key views were that: imatinib blood level measured between days seven and 29 of treatment could be a prognostic indicator and an important baseline for evaluating subsequent measurements; an imatinib trough plasma threshold for optimal response of 1,000ng/ml has been proposed but needs further validation; there is insufficient evidence to define any relationship between imatinib plasma levels and adverse events; and, although it is not yet possible to define and validate a comprehensive algorithm for the application of BLT in clinical practice, a working model has been developed. Pan-European collaboration, data pooling and initiation of a prospective clinical trial would be important steps in addressing current uncertainties. KeywordsBlood level testing, therapeutic drug monitoring, chronic myeloid leukaemia, European Treatment and Outcome Study (EUTOS), imatinib, tyrosine kinase inhibitor, algorithm Disclosure: François-Xavier Mahon and Mathieu Molimard have been consultants and participated in scientific advisory boards for Novartis and have received a grant from Novartis to perform imatinib blood level testing in European patients. Kajetana Foryciarz has been a consultant for and received honoraria as a speaker from Novartis and Bristol-Myers Squibb (BMS). Andrea Davies has received research funding from Novartis. Carmen Fava has no conflicts of interest to declare. Eberhard Schleyer has received a research grant from Novartis to conduct imatinib blood level testing. Peter Schuld is an employee of Novartis. François Guilhot has received a research grant from Novartis and honoraria as a speaker from BMS and Novartis.

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Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability

Cited by 102 publications

References 51 publications

A Long-term Prospective Population Pharmacokinetic Study on Imatinib Plasma Concentrations in GIST Patients

A Long-term Prospective Population Pharmacokinetic Study on Imatinib Plasma Concentrations in GIST Patients

Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia

Imatinib Blood Level Testing – Current Perspectives and Key Questions

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