Stations structure activity relationship of imatinib

Qualitative Structure-Activity Relationship (SAR) SAR . imatinib, Gleevec (in the United States) and Glivec (in Europe). HES As flavonoids, coumarins are largely distributed in plants, like Apiaceae and. Rutaceae. [1] S.R. Hubbard, J.H. Till, Protein tyrosine kinase structure and function, Annu. Rev. [3] P. Ramirez, J.F. DiPersio, Therapy options in imatinib failures, Oncologist 13 () – [4] B.C. Chen Structure-activity relationship studies toward the discovery of 14, Merck & Co., Inc., Whitehouse Station, NJ, USA, , p. Design, Syntheses and SAR of Inhibitors Targeting the TI-ABL Mutation Imatinib (Gleevec, Novartis AG) is frontline therapy for all phases of CML in.

Furthermore, the in vivo intracellular pharmacokinetics of imatinib was explored in five patients. Oral clearance was influenced by body weight, age, sex and disease diagnosis. Conclusion Because of the high pharmacokinetic variability of imatinib and the reported relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be further investigated.

Imatinib was rationally designed to inhibit the Bcr-Abl tyrosine kinase.

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

This fusion oncoprotein results from a t 9,22 translocation which gives rise to the Philadelphia chromosome, the hallmark of CML and of some acute lymphoblastic leukaemias ALL [ 4 ]. Imatinib was also found to be a potent inhibitor of the autophosphorylation of two additional tyrosine kinases, namely, c-Kit, involved in the oncogenesis of GIST [ 5 ], and platelet-derived growth factor receptor PDGFRinvolved, for example, in the pathogenesis of the hypereosinophilic syndrome [ 6 ].

However, imatinib must be taken indefinitely and is not devoid of toxicity. Moreover, resistance or escape from disease control occurs in a significant number of patients. Resistance to imatinib is variable, especially in CML during the accelerated or blastic phase [ 4910 ]. Activation of alternative survival signalling pathways can also arise [ 1112 ].

The probability of harbouring resistance mutations increases with disease progression as a consequence of increased tumour cell abundance [ 13 ]. In addition, imatinib has recently been shown to be a substrate of the organic cation influx transporter 1 hOCT1 [ 19 ].

Accordingly, imatinib concentrations in patients whose dosage was progressively increased were substantially lower than those at the beginning of treatment.

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

Because of this discrepancy, further investigation of the pharmcokinetics of imatinib is merited, with particular respect to the identification of individual kinetic determinants that could modulate clinical response [ 32 ].

Additionally, resistance could also be directly or indirectly caused by an increase in cellular efflux of imatinib, mediated mainly by the drug transporter P-gp P-glycoprotein Mahon et al, ; Widmer et al,or by a decrease in cellular influx, mediated by the uptake carrier hOCT1 organic cation transporter Thomas et al, ; Crossman et al, ; Wang et al, Finally, nonadherence to imatinib dosage regimen may also play a role in resistance Tsang et al, A given dose therefore yields very different circulating concentrations between patients Widmer et al, ; Larson et al,possibly favouring the selection of resistant cellular clones in case of subtherapeutic drug exposure.

Several pharmacokinetic PK studies have been carried out for imatinib. Some have been able to verify the influence of factors such as weight, albuminaemia, haemoglobinaemia or ABCB1 MDR1 polymorphism on its PK Judson et al, ; Schmidli et al, ; Gurney et al, but not of those such as hepatic enzymes or impaired liver or kidney function Widmer et al, ; Gibbons et al, ; Ramanathan et al, Furthermore, recent evidence suggests that steady-state trough imatinib plasma concentration TPC at initiation of therapy is a significant predictor of complete cytogenetic and major molecular responses Larson et al, Interestingly, recent studies have begun to investigate the free drug exposure of imatinib Delbaldo et al, ; Widmer et al, The study from Delbado also explored the relationship between drug exposure area under the curve, AUC and effect.

It showed that unbound drug exposure was correlated to the haematological toxicity absolute neutrophil countbut it did not find significant association with treatment efficacy in GIST patients.

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However, the modulating influence of tumour genetics on the concentration—effect relationship of imatinib, and similar new targeted anticancer drugs, certainly deserves additional evaluation. The aims of this clinical investigation were as follows: For the present analysis, plasma samples were considered corresponding to routine visits only.

Informed written consent was obtained from all the participants. The population PK analysis of these data has been published elsewhere Widmer et al, The patients included in the present analysis were 38 with GIST and 20 with CML, who received imatinib at various dosage regimens — mg daily.

Peripheral blood samples, obtained under steady-state conditions, were drawn periodically at 1- to 6-month intervals on follow-up visits, along with routine laboratory tests.

In addition to accurate dosing and sampling time information, a comprehensive set of demographic and biological data were recorded for each patient, including plasma AGP Widmer et al, Imatinib concentration was measured using a validated method by high-performance liquid chromatography after solid phase extraction Widmer et al, Genomic DNA was extracted from sections of paraffin-embedded tumour blocks. Assessment of imatinib exposure On the basis of model purposely developed at the time of our population PK study nonlinear mixed effects model; NONMEM Widmer et al,individual post hoc Bayesian estimates of PK parameters were derived for all samples.

Moreover, free parameters i. Assessment of clinical response The therapeutic response was determined at the time of routine follow-up visits. As standardised evaluation of typical side effects was not systematically available in our patient's population e. National Cancer Institute's Common Toxicity Criteria, NCI-CTCthe number of side effects experienced by patients was considered instead as a surrogate outcome for toxicity summarised in a 4-point scale; 0, 1, 2 and 3 or more side effects.