Pharmacokinetic-Pharmacodynamic Relationships of Imatinib and Its Main Metabolite in Patients with Advanced Gastrointestinal Stromal Tumors

Delbaldo, Catherine; Chatelut, Étienne; Ré, Micheline; Deroussent, Alain; Séronie-Vivien, Sophie; Jambu, A.; Berthaud, P.; Cesne, Axel Le; Blay, Jean‐Yves; Vassal, Gilles

doi:10.1158/1078-0432.ccr-05-2596

Cited by 140 publications

(110 citation statements)

References 26 publications

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“…In addition, ORM1 has been shown to enhance endothelial cell migration and capillary tube formation in vitro (40). Moreover, several reports suggested that the serum levels of α-1-acid glycoprotein influenced the pharmacokinetics (PK)/pharmacodynamics (PD) of chemotherapy drugs such as docetaxel, PTX and imatinib (41)(42)(43)(44). As these reports remarked, α-1-acid glycoprotein may function as a carrier of PTX from the serum into the liver via the α-1-acid glycoprotein receptors, and this might result in the enhancement of the PTX metabolism.…”

Section: Discussionmentioning

confidence: 99%

Identification of proteomic and metabolic signatures associated with chemoresistance of human epithelial ovarian cancer

Wang

Yin

et al. 2016

International Journal of Oncology

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Abstract. Emerging drug resistance in epithelial ovarian cancer (EOC) thwarted progress in platinum-based chemotherapy, resulting in increased mortality, morbidity and healthcare costs. The aim of this study was to detect the responses induced by chemotherapy at protein and metabolite levels, and to search for new plasma markers that can predict resistance to platinum-based chemotherapy in EOC patients, leading to improved clinical response rates. Serum samples were collected and subjected to proteomic relative quantitation analysis and metabolomic analysis. Differentially expressed proteins and metabolites were subjected to bioinformatics and statistical analysis. Proteins that played a key role in platinum resistance were validated by western blotting and enzyme-linked immunosorbent assay (ELISA). Metabolites that were the main contributors to the groups and closely with clinical characteristics were identified based on the database using nuclear magnetic resonance (NMR). In total, 248 proteins from two independent experiments were identified using isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic approach. Among them, FN1, SERPINA1, GPX3 and ORM1 were chosen for western blotting and ELISA validation. Platinum resistance likely associated with differentially expressed proteins and FN1, SERPINA1 and ORM1 may play a positive role in chemotherapy. HPLC-MS analysis of four groups revealed a total of 25,800 metabolic features, of which six compounds were chosen for candidate biomarkers and identified based on the database using NMR. The metabolic signatures of normal control (NC), platinum-sensitive (PTS) and platinum-resistant (PTR) groups were clearly separated from each other.Those findings may provide theoretical clues for the prediction of chemotherapeutic response and reverse of drug resistance, even lead to novel targets for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Identification of proteomic and metabolic signatures associated with chemoresistance of human epithelial ovarian cancer

Wang

Yin

et al. 2016

International Journal of Oncology

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“…These data suggest that patients who can tolerate high-dose imatinib achieve superior cytogenetic and molecular responses compared with those who need dose modification and suggest that the number of days off medication may adversely impact outcomes. Other confounding factors that may contribute to a patient's ability to maintain dose intensity (eg, high plasma ␣-1-acid glycoprotein levels or other factors associated with increased adverse events [20][21][22][23] ) were not investigated in this study. In this study, imatinib 800 mg/day induced earlier CCyR and MMR in patients with newly diagnosed CML-CP.…”

Section: Discussionmentioning

confidence: 99%

Phase III, Randomized, Open-Label Study of Daily Imatinib Mesylate 400 mg Versus 800 mg in Patients With Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase Using Molecular End Points: Tyrosine Kinase Inhibitor Optimization and Selectivity Study

Cortes

Baccarani

Guilhot

et al. 2010

JCO

260

233

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A B S T R A C T PurposeTo evaluate the safety and efficacy of initial treatment with imatinib mesylate 800 mg/d (400 mg twice daily) versus 400 mg/d in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Patients and MethodsA total of 476 patients were randomly assigned 2:1 to imatinib 800 mg (n ϭ 319) or 400 mg (n ϭ 157) daily. The primary end point was the major molecular response (MMR) rate at 12 months. ResultsAt 12 months, differences in MMR and complete cytogenetic response (CCyR) rates were not statistically significant (MMR, 46% v 40%; P ϭ .2035; CCyR, 70% v 66%; P ϭ .3470). However, MMR occurred faster among patients randomly assigned to imatinib 800 mg/d, who had higher rates of MMR at 3 and 6 months compared with those in the imatinib 400-mg/d arm (P ϭ .0035 by log-rank test). CCyR also occurred faster in the 800-mg/d arm (CCyR at 6 months, 57% v 45%; P ϭ .0146). The most common adverse events were edema, gastrointestinal problems, and rash, and all were more common in patients in the 800-mg/d arm. Grades 3 to 4 hematologic toxicity also occurred more frequently in patients receiving imatinib 800 mg/d. ConclusionMMR rates at 1 year were similar with imatinib 800 mg/d and 400 mg/d, but MMR and CCyR occurred earlier in patients treated with 800 mg/d. Continued follow-up is needed to determine the clinical significance of earlier responses on high-dose imatinib.

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“…25 Indeed, Delbaldo et al reported a correlation between increased AAG levels and decreased imatinib clearance. 26 In order to conclusively assess the possibility of pharmacokinetic resistance arising from modulation of drug disposition via changes in protein binding, metabolism, or transport, long-term pharmacokinetic studies must be embarked upon. Assessment of steady-state pharmacokinetics at monthly intervals would allow for determination of long-term changes in drug clearance.…”

Section: Discussionmentioning

confidence: 99%

Lack of ABC transporter autoinduction in mice following long-term exposure to imatinib

Gardner

Sparreboom²,

Verweij³

et al. 2008

Cancer Biology & Therapy

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This manuscript has been published online, prior to printing.Once the issue is complete and page numbers have been assigned, the citation will change accordingly.Purpose: Chronic imatinib exposure has been shown to result in upregulation of the ABCB1 (P-glycoprotein) and ABCG2 (BCRP) transporters in vitro, for which imatinib is a substrate. This finding, along a trend towards increasing imatinib clearance over time in patients, has resulted in the suggestion that pharmacokinetic resistance may be contributing to eventual treatment failure. Here, we sought to determine the effects of long-term imatinib exposure on apparent oral clearance and transporter expression in vivo.Results: Plasma and liver concentrations of imatinib did not change significantly (p > 0.1) over the course of treatment, suggesting that steady-state had been reached. There was no increase in Abcb1 or Abcg2 expression in liver samples, whereas expression of these transporters in intestinal samples was highly variable, and no increase was apparent.Methods: Male BALB/c mice were treated daily-times 5 with oral imatinib at a dose of 50 mg/kg for 4 consecutive weeks. Imatinib concentrations were measured in plasma and liver tissue prior to treatment and following each week of dosing. Western blotting of liver and intestinal tissue lysates was performed to assess expression of Abcb1 and Abcg2.Conclusions: Imatinib does not appear to cause upregulation of ABC transporters in the hepatic and intestinal compartments in mice. These data do not support the possibility that autoinduction contributes to the development of resistance to imatinib.

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Pharmacokinetic-Pharmacodynamic Relationships of Imatinib and Its Main Metabolite in Patients with Advanced Gastrointestinal Stromal Tumors

Cited by 140 publications

References 26 publications

Identification of proteomic and metabolic signatures associated with chemoresistance of human epithelial ovarian cancer

Identification of proteomic and metabolic signatures associated with chemoresistance of human epithelial ovarian cancer

Phase III, Randomized, Open-Label Study of Daily Imatinib Mesylate 400 mg Versus 800 mg in Patients With Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase Using Molecular End Points: Tyrosine Kinase Inhibitor Optimization and Selectivity Study

Lack of ABC transporter autoinduction in mice following long-term exposure to imatinib

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