Clinical Pharmacokinetics of Imatinib

Peng, Bin; Lloyd, Peter; Schran, Horst

doi:10.2165/00003088-200544090-00001

Cited by 583 publications

(528 citation statements)

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“…The pharmacokinetics of imatinib has been extensively studied in Caucasian CML patients [17][18][19][20][21] . However, few studies have been reported on naïve Chinese.…”

Section: Discussionmentioning

confidence: 99%

“…Based on higher drug exposure in Chinese patients and dose-proportional imatinib exposure [18,19] , a rational conjecture is that Chinese patients would have a better disease response. We can infer that the patients in our studies had have better disease responses, even though CMR was not monitored in the IRIS study, in which BCR-ABL transcripts in the blood samples were measured only at 1 and 4 years in 124 patients who had a CCyR.…”

Section: Discussionmentioning

confidence: 99%

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Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients

Chen

et al. 2010

Acta Pharmacol Sin

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Aim: To investigate the pharmacokinetics of imatinib in Chinese chronic myelogenous leukemia (CML) patients. Methods: Fourty-six naïve Chinese CML patients treated with imatinib (400 and 600 mg daily, n=36 and 10, respectively) were recruited. The correlations of imatinib (400 mg) trough plasma concentrations (C mins ) with the patients' characteristics and responses were analyzed. Results: The overall mean (±SD, CV%) steady-state C mins for imatinib at 400 mg (n=36) and 600 mg (n=10) daily was 1325.61 ng/mL (±583.53 ng/mL; 44%) and 1550.90 ng/mL (±462.63 ng/mL; 30%), respectively, and no statistically significant differences were found between them (P=0.267). At 400 mg daily, female patients had significantly higher C mins than the male patients (P=0.048), and molecular responses were not correlated with imatinib C mins , but they were correlated with time elapsed before imatinib therapy. Conclusion:The results suggest that Chinese CML patients have higher imatinib C mins than their Caucasian counterparts and that the optimal initial imatinib dose for them requires further investigation.

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“…The pharmacokinetics of imatinib has been extensively studied in Caucasian CML patients [17][18][19][20][21] . However, few studies have been reported on naïve Chinese.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients

Chen

et al. 2010

Acta Pharmacol Sin

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“…It should be noted that the number of patients in this study is small and that the study should be regarded as a pilot study. There might be a number of confounding factors such as different disease phase, that some patients were phenotyped during imatinib therapy and other factors might as well influence imatinib pharmacokinetics such as body weight and α-acid glycoprotein plasma levels [4,6,17,18].…”

Section: Discussionmentioning

confidence: 99%

“…In the liver, imatinib is metabolized mainly by cytochrome P450 (CYP) 3A4 and 3A5, although CYP1A1, CYP1A2, CYP1B1, CYP2D6, CYP2C9, and CYP2C19 might also contribute to a minor extent [4,5]. The main metabolite in plasma, CGP74588, is mainly formed by CYP3A4 and present in concentrations of around 20% of that of the parent drug but with a large interindividual variation.…”

Section: Introductionmentioning

confidence: 99%

CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity

Gréen

Skoglund

Rommel

et al. 2010

Eur J Clin Pharmacol

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Purpose: Imatinib is currently used for the treatment of chronic myeloid leukemia (CML) patients. The main metabolite CGP74588 has similar potency to that of imatinib and is a product of CYP3A4 and CYP3A5 metabolism. However, the clinical significance of the metabolism on therapeutic response and pharmacokinetics is still unclear. We designed this study to investigate the role of the CYP3A activity in the response to imatinib therapy.Methods: Fourteen CML patients were phenotyped for in vivo CYP3A activity using quinine as a probe drug. The plasma concentration ratio of quinine and its CYP3A metabolite was used for assessing CYP3A activity. The patients were divided into complete molecular responders with undetectable levels of BCR-ABL transcripts after 12 months of therapy and into partial molecular responders who had failed to achieve a complete molecular response.Results: Patients that achieved complete molecular response showed significantly (MannWhitney U-test, p = 0.013) higher in vivo CYP3A activity (median quinine metabolic ratio = 10.1) than patients achieving partial molecular response (median = 15.9).Conclusions: These results indicate a clinical significance of the CYP3A activity and its metabolic products in CML patients treated with imatinib.

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“…These doses of imatinib have been shown to reach plasma concentrations comparable to those in CML patients treated with 400 mg imatinib daily. [20][21][22] For in vitro studies, 10 mM imatinib stock solutions in dimethylsulfoxide (DMSO; Fluka, Buchs, Switzerland) were frozen at Ϫ20°C. Indicated concentrations were added to the cell cultures.…”

Section: Imatinib Mesylate and Treatment Of Micementioning

confidence: 99%

Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections

Mumprecht

Matter

Pavelic

et al. 2006

Blood

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IntroductionImatinib mesylate (STI571, Glivec; Novartis Pharma AG, Basel, Switzerland) selectively inhibits the tyrosine kinases (TKs) ABL, BCR/ABL, ARG, PDGF-R ␣ and ␤, and c-KIT. Constitutive activation of these TKs has been documented in chronic myeloid leukemia (CML), Philadelphia chromosome-positive (Ph ϩ ) acute lymphocytic leukemia, myeloproliferative disorders due to chromosomal rearrangements in PDGF-R, and gastrointestinal stromal tumors with mutations in c-KIT. [1][2][3][4] In these diseases, blocking of TKs with imatinib is very efficient and substantially improves clinical outcome.Since TKs are involved in various intracellular signaling pathways, it is not surprising that imatinib treatment affects immune responses. Clinical observations have suggested that imatinib treatment correlates with a reversible dose-dependent lymphopenia and hypogammaglobulinemia. 5 Experimental in vitro studies have demonstrated that imatinib inhibited the development of human CD34 ϩ progenitor cell-derived dendritic cells (DCs). In addition, DCs exposed to imatinib were less potent in inducing cytotoxic T-cell (CTL) responses against tumor and recall antigens. 6 However, results of the effect of imatinib on DC maturation are controversial. Other experiments have suggested a normal maturation but reduced expansion of DCs in mice when stimulated with Flt3L. 7 Further, it has been shown that treating DCs in vitro with imatinib enhanced antigen-presenting cell function and overcame tumor-induced CD4 ϩ T-cell tolerance. 8 In addition, several in vitro studies using T cells isolated from human peripheral blood have demonstrated a dose-dependent reduction of T-cell proliferation in the presence of imatinib. 1,9,10 These results raise the possibility that imatinib could affect normal immune functions through TK inhibition. TKs play a prominent role in T-cell receptor (TCR) and B-cell receptor (BCR) signal transduction, and, thus, it is conceivable that imatinib may interfere with this process. TCR ligation triggers a signaling cascade that includes activation of the TKs Lck, ZAP70, and Ltk. A recent study has reported the requirement of c-ABL and ARG TKs for TCR-dependent transcriptional activation. 11 c-ABL is activated by Lck and then leads to the phosphorylation of ZAP70. It remains unclear whether c-ABL activates only ZAP70 or also activates other downstream proteins. 12 However, primary T cells lacking functional ABL TKs showed decreased IL-2 production and cell proliferation in response to TCR stimulation. 11 Comparably, it has been shown that ABL phosphorylates the BCR coreceptor CD19, suggesting a role for ABL in the regulation of B-cell proliferation. 13 Taken together, these experiments suggest that imatinib treatment in vivo may crucially influence antiviral CD8 ϩ T-and B-cell responses. However, physiologic consequences of imatinib treatment on protective immune response have not yet been demonstrated.Primary infection with lymphocytic choriomeningitis virus (LCMV), a noncytopathic RNA virus, is controlled almost ex...

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Clinical Pharmacokinetics of Imatinib

Cited by 583 publications

References 58 publications

Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients

Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients

CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity

Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections

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