Abstract:O mesilato de imatinibe (MI) é atualmente o tratamento de escolha da Leucemoa Mielóide Crônica (LMC), mas, apesar dos excelentes resultados, não é capaz de erradicar completamente a doença, podendo ocorrer resistência ao tratamento. O mecanismo mais conhecido de resistência é o desenvolvimento de mutações do BCR-ABL, que impedem a ação ligação adequada do imatinibe à quinase, além de amplificação gênica e evolução clonal. No entanto, há uma série de outros mecanismos envolvidos e ainda pouco estudados, como al… Show more
“…(9,15) Sensitive methods to determine imatinib in biological fluids are required to conduct TDM, pharmacokinetics and metabolic studies. (25) …”
Section: Therapeutic Monitoring Of Imatinibmentioning
confidence: 99%
“…(9) According to Larson et al (14) patients with lower imatinib plasma levels had higher rates of discontinuation and a higher percentage of patients stopped treatment because of unsatisfactory therapeutic effect. These data suggest that patients are more likely to achieve a satisfactory level of response to therapy or an improvement in response rates if an appropriate concentration of trough imatinib is reached and maintained.…”
Section: Imatinib Plasma Levels and Their Clinical Applicationmentioning
confidence: 99%
“…( 5 , 10 , 12 ) Resistance to imatinib can be multifactorial, presenting problems in the drug pharmacokinetics, mediators of cellular drug uptake, like the human organic cation transporter 1 (hOCT1) protein and mutations. Mutations are more frequent in secondary rather than primary resistance, ( 9 ) with the most common being deletion of BCR-ABL by amplification of this oncogene, mutation of the binding site of BCR-ABL by altered metabolism of imatinib, and by a transport mechanism. ( 5 , 10 , 12 ) Since 2001 with the first report of a mutation in resistant patients, more than 70 others have been reported.…”
Section: Pharmacodynamics and Pharmacokinetics Of Imatinibmentioning
confidence: 99%
“…( 7 , 8 ) Allogeneic BMT is considered the only curative treatment for CML, with a 65% chance of cure. ( 9 , 10 ) However, only 15% to 30% of the patients can be submitted to transplantation due to the lack of histocompatible donors and the advanced age of the patients who are usually affected by the disease.…”
Section: Introductionmentioning
confidence: 99%
“…Imatinib plasma concentrations outside the recommended therapeutic levels may be related to absorption variations, biotransformation or elimination due to genetic and environmental factors, interactions with other drugs or associated to lack of patient adherence. ( 9 , 14 , 15 ) Considering the positive impact of the therapeutic monitoring of imatinib in the treatment of CML, it is necessary to know the clinical aspects of imatinib pharmacokinetics as well as to establish monitoring of plasma levels in patients with CML. This study aims to review the clinical and laboratory aspects of therapeutic monitoring of imatinib in Ph + CML patients.…”
Imatinib has proved to be effective in the treatment of chronic myeloid leukemia, but plasma levels above 1,000 ng/mL must be achieved to optimize activity. Therapeutic drug monitoring of imatinib is useful for patients that do not present clinical response. There are several analytical methods to measure imatinib in biosamples, which are mainly based on liquid chromatography with mass spectrometric or diode array spectrophotometric detection. The former is preferred due to its lower cost and wider availability. The present manuscript presents a review of the clinical and analytical aspects of the therapeutic drug monitoring of imatinib in the treatment of chronic myeloid leukemia. The review includes references published over the last 10 years. There is evidence that the monitoring of plasmatic levels of imatinib is an useful alternative, especially considering the wide pharmacokinetic variability of this drug.
“…(9,15) Sensitive methods to determine imatinib in biological fluids are required to conduct TDM, pharmacokinetics and metabolic studies. (25) …”
Section: Therapeutic Monitoring Of Imatinibmentioning
confidence: 99%
“…(9) According to Larson et al (14) patients with lower imatinib plasma levels had higher rates of discontinuation and a higher percentage of patients stopped treatment because of unsatisfactory therapeutic effect. These data suggest that patients are more likely to achieve a satisfactory level of response to therapy or an improvement in response rates if an appropriate concentration of trough imatinib is reached and maintained.…”
Section: Imatinib Plasma Levels and Their Clinical Applicationmentioning
confidence: 99%
“…( 5 , 10 , 12 ) Resistance to imatinib can be multifactorial, presenting problems in the drug pharmacokinetics, mediators of cellular drug uptake, like the human organic cation transporter 1 (hOCT1) protein and mutations. Mutations are more frequent in secondary rather than primary resistance, ( 9 ) with the most common being deletion of BCR-ABL by amplification of this oncogene, mutation of the binding site of BCR-ABL by altered metabolism of imatinib, and by a transport mechanism. ( 5 , 10 , 12 ) Since 2001 with the first report of a mutation in resistant patients, more than 70 others have been reported.…”
Section: Pharmacodynamics and Pharmacokinetics Of Imatinibmentioning
confidence: 99%
“…( 7 , 8 ) Allogeneic BMT is considered the only curative treatment for CML, with a 65% chance of cure. ( 9 , 10 ) However, only 15% to 30% of the patients can be submitted to transplantation due to the lack of histocompatible donors and the advanced age of the patients who are usually affected by the disease.…”
Section: Introductionmentioning
confidence: 99%
“…Imatinib plasma concentrations outside the recommended therapeutic levels may be related to absorption variations, biotransformation or elimination due to genetic and environmental factors, interactions with other drugs or associated to lack of patient adherence. ( 9 , 14 , 15 ) Considering the positive impact of the therapeutic monitoring of imatinib in the treatment of CML, it is necessary to know the clinical aspects of imatinib pharmacokinetics as well as to establish monitoring of plasma levels in patients with CML. This study aims to review the clinical and laboratory aspects of therapeutic monitoring of imatinib in Ph + CML patients.…”
Imatinib has proved to be effective in the treatment of chronic myeloid leukemia, but plasma levels above 1,000 ng/mL must be achieved to optimize activity. Therapeutic drug monitoring of imatinib is useful for patients that do not present clinical response. There are several analytical methods to measure imatinib in biosamples, which are mainly based on liquid chromatography with mass spectrometric or diode array spectrophotometric detection. The former is preferred due to its lower cost and wider availability. The present manuscript presents a review of the clinical and analytical aspects of the therapeutic drug monitoring of imatinib in the treatment of chronic myeloid leukemia. The review includes references published over the last 10 years. There is evidence that the monitoring of plasmatic levels of imatinib is an useful alternative, especially considering the wide pharmacokinetic variability of this drug.
Gene breakpoint cluster regionBCR-ABL Gene híbrido obtido da fusão de partes dos genes BCR e ABL
Bcr-AblProteína híbrida codificada pelo gene BCR-ABL
CYP 3A4Gene citocromo p450 subfamília 3A4 Cyp3a4 Isoenzima da subfamília 3A4 do citocromo P450 DNA Ácido desoxirribonucleico IFN-α Interferon alfa IRIS International Randomized Interferon versus STI571 LLA Leucemia linfóide aguda LMA Leucemia mielóide aguda LMC Leucemia mielóide crônica M-bcr Major breakpoint cluster region, ponto de quebra maior m-bcr Minor breakpoint cluster region, ponto de quebra menor MDR1 Gene de resistência à múltiplas drogas MO Medula óssea OMS Organização mundial da saúde PCR Reação da cadeia da polimerase xxviii Ph Cromossomo Filadélfia PI3K Phosfatidil-inosito-3-kinase RQ-PCR Reação da cadeia da polimerase quantitativa RT-PCR Reação em cadeia da polimerase por transcrição reversa RCC Resposta citogenética completa RCP Resposta citogenética parcial RCM Resposta citogenética maior RCMin Resposta citogenética mínima RHC Resposta hematológica completa RMC Resposta molecular completa RMM Resposta molecular maior SG Sobrevida global SLP Sobrevida livre de progressão TCTH Transplante de células tronco hematopoéticas TKR Tyrosine kinase receptor, receptor tirosina quinase
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