Pharmacokinetics and Pharmacodynamics of Imatinib in a Phase I Trial With Chronic Myeloid Leukemia Patients

Peng, Bin; Hayes, M.; Resta, Debra; Racine-Poon, Amy; Druker, Brian J.; Talpaz, Moshe; Sawyers, Charles L.; Rosamilia, M.; Ford, John M.; Lloyd, Peter; Capdeville, Renaud

doi:10.1200/jco.2004.03.050

Cited by 422 publications

(373 citation statements)

References 17 publications

(14 reference statements)

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“…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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Section: Discussionmentioning

confidence: 99%

“…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%

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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“…Development and application of imatinib that targets BCR/ABL oncoprotein is an important milestone for the treatment of (CML). Imatinib binds to adenosine triphosphate (ATP)-binding site of BCR/ABL and inhibits phosphorylation of BCR/ABL targets that prevent leuke-mogenesis [8]. But, although very high hematological and cytogenetical responses were obtained in response to imatinib in the beginning, drug resistance was the major drawback in imatinib-based protocols [9].…”

Section: Introductionmentioning

confidence: 99%

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

et al. 2011

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Sphingolipids are bioeffector molecules that control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramides, the central molecule of sphingolipid metabolism, are inducer of apoptosis and inhibitors of proliferation. Sphingosine-1-phosphate (S1P) and glucosyleceramide, converted from ceramides by sphingosine kinase-1 (SK-1) and glucosyleceramide synthase (GCS) enzymes, respectively, inhibit apoptosis and develop resistance to chemotherapeutic drugs. In this study, we examined the therapeutic potentials of bioactive sphingolipids in chronic myeloid leukemia (CML) alone and in combination with dasatinib in addition to investigate the roles of ceramide-metabolizing genes in dasatinib-induced apoptosis. Cytotoxic effects of dasatinib, C8:ceramide, PDMP, and SK-1 inhibitor were determined by XTT cell proliferation assay. Changes in caspase-3 enzyme activity and mitochondrial membrane potential (MMP) were measured using caspase-3 colorimetric assay and JC-1 MMP detection kit. Expression levels of ceramide-metabolizing genes were examined by qRT-PCR. Application of ceramide analogs and inhibitors of ceramide clearance genes decreased cell proliferation and induced apoptosis. Targeting bioactive sphingolipids towards generation/accumulation of ceramides increased apoptotic effects of dasatinib, synergistically. It was shown for the first time that dasatinib induces apoptosis through downregulating expression levels of antiapoptotic SK-1 but not GCS, and upregulating expression levels of ceramide synthase (CerS) genes, especially CerS1, in K562 cells. On the other hand, dasatinib downregulates expression levels of both GCS and SK-1 and upregulate apoptotic CerS2, −5 and −6 genes in Meg-01 cells. Increasing endogenous ceramide levels and decreasing prosurvival lipids, S1P, and GC, can open the way of more effective treatment of CML.

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“…The maximum plasma concentration measured in CML patients after a single administration of 400 mg imatinib is about 3.2 M but can reach 6.2 M at steady state with 400 mg imatinib administered twice daily. 30 Therefore, the imatinib concentrations used in our experiments are in the therapeutic range. In the presence of imatinib, significantly lower numbers of DCs were generated (1.1 ϫ 10 6 Ϯ 0.2 ϫ 10 6 ) compared with nontreated controls (4.0 ϫ 10 6 Ϯ 0.4 ϫ 10 6 ) (P Ͻ .001).…”

Section: Dcs Generated In Vitro In the Presence Of Imatinib Are Not Fmentioning

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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Pharmacokinetics and Pharmacodynamics of Imatinib in a Phase I Trial With Chronic Myeloid Leukemia Patients

Cited by 422 publications

References 17 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

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

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

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