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1.
BMC Pharmacol Toxicol ; 21(1): 70, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32993794

RESUMO

BACKGROUND: Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia. METHODS: Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300-400 mg BID (cohort - 1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3 + 3 rule ("Rolling Six"), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase. RESULTS: Twenty-four patients with ALL (n = 11) or AML (n = 12) or CML-BP (n = 1) were enrolled. All patients had failed one (n = 5) or more lines of therapy (n = 5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. CONCLUSIONS: Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML. TRIAL REGISTRATION: ClinicalTrials.gov , identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118 .


Assuntos
Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Leucemia/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Quinolinas/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Leucemia/genética , Leucemia/metabolismo , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinolinas/farmacocinética , Quinolinas/farmacologia , Recidiva , Proteínas Quinases S6 Ribossômicas/metabolismo , Fatores de Transcrição/genética , Resultado do Tratamento
2.
Expert Rev Clin Pharmacol ; 11(3): 219-231, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29076384

RESUMO

INTRODUCTION: The tyrosine kinase inhibitor (TKI) imatinib was rationally designed to target BCR-ABL1 which is constitutively activated in chronic myeloid leukemia (CML). Following the tremendous success in adults, imatinib also became licensed for treatment of CML in minors. The rarity of pediatric CML hampers the conduction of formal trials. Thus, imatinib is still the single TKI approved for CML treatment in childhood. Areas covered: This review attempts to provide an overview of the literature on pharmacology, pharmacokinetic, and pharmacogenetic of imatinib concerning pediatric CML treatment. Articles were identified through a PubMed search and by reviewing abstracts from relevant hematology congresses. Additional information was provided from the authors' libraries and expertise and from our own measurements of imatinib trough plasma levels in children. Pharmacokinetic variables (e.g. alpha 1-acid glycoprotein binding, drug-drug/food-drug interactions via cytochrome P450 3A4/5, cellular uptake mediated via OCT-1-influx variations and P-glycoprotein-mediated drug efflux) still await to be addressed in pediatric patients systematically. Expert commentary: TKI response rates vary among different individuals and pharmacokinetic variables all can influence CML treatment success. Adherence to imatinib intake may be the most prominent factor influencing treatment outcome in teenagers thus pointing towards the potential benefits of regular drug monitoring.


Assuntos
Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Adolescente , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Criança , Monitoramento de Medicamentos , Interações Alimento-Droga , Proteínas de Fusão bcr-abl , Humanos , Mesilato de Imatinib/farmacocinética , Mesilato de Imatinib/farmacologia , Adesão à Medicação , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
3.
Biomed Res Int ; 2014: 637059, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25025064

RESUMO

Central nervous system (CNS) involvement is a severe complication of BCR-ABL-positive leukemia after allogenic stem cell transplantation (alloSCT) associated with fatal outcome. Although second-generation tyrosine-kinase inhibitors (TKI) such as nilotinib have shown activity in systemic BCR-ABL(+) disease, little data exists on their penetration and efficacy within the CNS. Four patients (3 male, 1 female; age 15-49) with meningeal relapse after alloSCT and subsequent treatment with nilotinib were identified. A total of 17 cerebrospinal fluid (csf) and serum samples were assessed for nilotinib concentration and patient outcome was recorded. Nilotinib concentrations showed a low median csf/plasma ratio of 0.53% (range 0.23-1.5%), yet pronounced clinical efficacy was observed with long-lasting responses (>1 year) in three patients. Comparison with historical data showed a trend towards superior efficacy of nilotinib versus imatinib. Despite poor csf penetration, nilotinib showed significant clinical activity in CNS relapse of BCR-ABL(+) leukemias. As nilotinib has a high protein-binding affinity, the low-protein concentration in csf could translate into a relatively higher amount of free and therefore active nilotinib in csf as compared to blood, possibly explaining the observed efficacy. Thus, treatment with a 2nd generation TKI warrants further investigation and should be considered in cases of CNS relapse of BCR-ABL-positive leukemia after alloSCT.


Assuntos
Sistema Nervoso Central/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Pirimidinas/administração & dosagem , Adolescente , Adulto , Benzamidas/administração & dosagem , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Piperazinas/administração & dosagem , Transplante de Células-Tronco/efeitos adversos , Transplante Homólogo/efeitos adversos
5.
Leuk Lymphoma ; 53(6): 1062-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22054287

RESUMO

Sorafenib is a multi-kinase inhibitor with activity against several intracellular kinases which may play a role in the pathogenesis of acute myeloid leukemia (AML). In vitro data and results from early clinical trials suggest that sorafenib might be an effective drug for the treatment of AML. However, clinical data are still sparse, and there are only a few reported cases of monotherapy. The aim of the present research was to collect clinical data on efficacy and safety in a systematic way by conducting a survey on clinical experience with sorafenib. Thirty institutions were asked to document all patients treated with sorafenib diagnosed with AML. Of all 29 evaluable patients, six (21%) responded to sorafenib containing treatment by achieving a complete remission (CR, n = 2) or complete remission with incomplete platelet recovery (CRi, n = 4). In 23 patients receiving sorafenib as monotherapy, the CRi rate amounted to 13% and no CRs were documented. Of the 18 FLT-ITD positive patients with sorafenib monotherapy, two patients achieved a CRi (11%). In five FLT3-ITD negative cases, one CRi was documented (20%). Our results suggest the potential ability of the drug to induce remissions in refractory or relapsed AML even when given as monotherapy.


Assuntos
Benzenossulfonatos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Padrões de Prática Médica/estatística & dados numéricos , Piridinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Benzenossulfonatos/efeitos adversos , Coleta de Dados , Feminino , Humanos , Leucemia Mieloide Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , Indução de Remissão , Estudos Retrospectivos , Sorafenibe , Resultado do Tratamento , Adulto Jovem
7.
J Neurooncol ; 96(3): 393-402, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19688297

RESUMO

A randomized, multicenter, open-label, phase 3 study of patients with progressive, recurrent glioblastoma multiforme (GBM) for whom front-line therapy had failed was conducted. This study was designed to determine whether combination therapy with imatinib and hydroxyurea (HU) has superior antitumor activity compared with HU monotherapy in the treatment of recurrent GBM. The target population consisted of patients with confirmed recurrent GBM and an Eastern Cooperative Oncology Group performance status of 0-2 who had completed previous treatment comprising surgical resection, irradiation therapy, and first-line chemotherapy (preferably temozolomide (TMZ) containing regimen) and who have progressed despite treatment. If first-line chemotherapy did not contain TMZ, a second completed chemotherapy was acceptable. The primary efficacy parameter was progression-free survival (PFS). The primary comparison of combination therapy versus monotherapy for PFS was not significant (adjusted P = 0.56). The hazard ratio (HR) (adjusted HR = 0.93) was not clinically relevant. The median PFS for the combination arm was low at 6 weeks and similar to the median PFS in the monotherapy arm (6 weeks). The 6-month PFS for the two treatment groups was very similar (5% in the combination arm vs. 7% in the monotherapy arm). No clinically meaningful differences were found between the two treatment arms, and the primary study end point was not met. Among the patients receiving imatinib, no adverse events were reported that were either previously unknown or unexpected as a consequence of the disease.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Hidroxiureia/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Fatores Etários , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Benzamidas , Terapia Combinada , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Temozolomida , Resultado do Tratamento , Adulto Jovem
9.
Curr Clin Pharmacol ; 3(3): 198-203, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18781906

RESUMO

BACKGROUND: Imatinib mesylate is used in combination with hydroxyurea (HU) in ongoing clinical phase II studies in recurrent glioblastoma multiforme (GBM). CYP3A4 enzyme-inducing antiepileptic drugs (EIAEDs) like carbamazepine, phenytoin, and oxcarbazepine--as well as non-EIAEDs like valproic acid, levetiracetam, and lamotrigine--are frequently used in patients with GBM. Since CYP3A4 is the major isozyme involved in the metabolism of imatinib, we investigated the influence of EIAEDs on imatinib pharmacokinetics (pk). METHODS: GBM patients received 600 mg imatinib p.o./o.d. in combination with 1.0 g HU p.o./o.d..together with either EIAEDs, non-EIAEDs, or no antiepileptic drug (non-AEDs) comedication. Trough plasma levels of imatinib and its active main metabolite N-desmethyl-imatinib (CGP74588) were determined biweekly in these patients, total 543 samples being collected from 224 patients (up to 6 times / patient). All three groups were compared to each other and with historical pharmacokinetic data obtained from patients with chronic myeloid leukemia (CML). RESULTS: Mean imatinib trough levels in patients not receiving AEDs ( 1404 ng/ml, CV 64%) and on non-EIAEDs (1374 ng/ml, CV 46%) were comparable with mean imatinib trough levels of the historical control group of CML patients (1400 ng/ml, CV 50%). Mean trough levels of imatinib were reduced up to 2.9-fold (477 ng/ml, CV 70%) in patients treated with EIAEDs. Only slight, but although significant differences were observed in the mean trough level of the metabolite CGP74588 between EIAED-, non-EIAED and no-AED patients, 240 ng/ml (CV 57%), 351 ng/ml (CV 34%) and 356 ng/ml (CV 52%), respectively. The corresponding mean level for CML patients was 300 ng/ml (CV 50%). CONCLUSION: Significant decreases of imatinib and CGP74588 trough levels were observed for patients receiving EIAEDs. The EIAED-induced reduction in trough imatinib levels can be avoided by switching to non-EIAEDs comedication or compensated by administering higher imatinib doses. In addition these data demonstrate that there is no significant difference in the pharmacokinetics of imatinib between patients with glioblastoma and CML.


Assuntos
Anticonvulsivantes/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Neoplasias Encefálicas/tratamento farmacológico , Citocromo P-450 CYP3A/biossíntese , Glioblastoma/tratamento farmacológico , Administração Oral , Adulto , Idoso , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/enzimologia , Cromatografia Líquida de Alta Pressão , Inibidores do Citocromo P-450 CYP3A , Relação Dose-Resposta a Droga , Interações Medicamentosas , Indução Enzimática , Feminino , Glioblastoma/complicações , Glioblastoma/enzimologia , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/sangue , Mesilato de Imatinib , Isoenzimas/antagonistas & inibidores , Isoenzimas/biossíntese , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/sangue , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Convulsões/etiologia , Convulsões/prevenção & controle , Adulto Jovem
10.
Cancer Chemother Pharmacol ; 61(5): 785-90, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17579865

RESUMO

BACKGROUND: The addition of etoposide to the CHOP protocol (CHOEP) has been shown to improve outcome in patients with aggressive non-Hodgkin's lymphoma. The intravenous administration of etoposide on three consecutive days represents a logistic problem and needs resources particular in the outpatient setting. This could be avoided by using etoposide capsules on days 2 and 3. However, the oral administration of cytotoxic agents is often affected by variable absorption and drug interactions. PATIENTS AND METHODS: We investigated the pharmacokinetic equivalency of oral and intravenous etoposide in ten patients (male, n=7; female, n=3; median age 56 years) with aggressive lymphomas. Treatment consisted of standard CHOP plus etoposide 100 mg/m2 given intravenously on day 1, and 200 mg/m2 orally on days 3 and 4. Samples from blood and urine were taken on days 1 (i.v. study) and 3 (p.o. study) before and after etoposide administration. Etoposide levels were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated with the TOPFIT computer program. RESULTS: Mean peak plasma level after intravenous etoposide was significantly higher compared to oral administration (16.3+/-3.7 vs. 12.0+/-4.2 microg/ml; P=0.015). The mean bioavailability of oral etoposide was 58+/-15% with an interpatient variability of 26%. Significant differences of bioavailability of oral etoposide between the used dose levels (350, 400 and 450 mg) were not observed. Mean AUC after a 100 mg/m2 intravenous and a 200 mg/m2 oral dose of etoposide were 74.0+/-18.3 and 84.9+/-29.6 microg h/ml (P=0.481). Interpatient variability of AUC was 25% for the intravenous route and 35% after oral intake. Urinary etoposide excretion as percentage of administered dose was 39.4+/-10.6% after intravenous infusion versus 35.4+/-9.4% after oral intake (P=0.422). Renal clearance was also very similar with intravenous and oral route (18.5+/-7.4 vs. 16.7+/-6.6 ml/min; P=0.546). CONCLUSION: The equivalency of AUC after 200 mg/m2 of oral and 100 mg/m2 of intravenous etoposide support the use of the oral preparation in patients treated with the CHOEP regimen, which makes the chemotherapy more convenient for the patients and help to reduce costs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Etoposídeo/farmacocinética , Linfoma não Hodgkin/tratamento farmacológico , Administração Oral , Área Sob a Curva , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Ciclofosfamida/administração & dosagem , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Software , Vincristina/administração & dosagem
11.
Cancer ; 109(9): 1897-904, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17377918

RESUMO

BACKGROUND: In previous experimental models, because of its ability to inhibit the activity of platelet-derived growth factor beta receptor, imatinib decreased the interstitial fluid pressure and improved the delivery and efficacy of anticancer drugs, including fluorouracil. The objective of this Phase I study was to define the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of imatinib in combination with fluorouracil and leucovorin in patients with chemotherapy-refractory gastrointestinal cancer. METHODS: A 3-patient cohort dose-escalating study design was used. Patients received leucovorin 200 mg/m2 followed by fluorouracil 2000 mg/m2 as a 24-hour infusion on Days 1 and 2 combined with imatinib on Days -4, -3, -2, -1, 1, 2, 3, and 4. Cycles were repeated every 2 weeks, and the imatinib dose was escalated from 300 mg daily to 700 mg daily in 100-mg steps. RESULTS: Thirty patients were enrolled at 5 dose levels. Frequent and dose-dependant National Cancer Institute Common Toxicity Criteria grade 1-4 adverse events with suspected relation to the treatment were anemia (43%), nausea (33%), fluid retention (27%), elevated serum gamma-glutamyl-transpeptidase (20%), and diarrhea. DLTs were severe neutropenia, central fluid retention, and severe nausea observed in 1 patient each, resulting in an MTD for imatinib of 600 mg per day. There were no differences in imatinib pharmacokinetics before or during chemotherapy. A minor response was observed; and signs of clinical activity, including the resolution of ascites and improvement in performance status, were noted in some patients. CONCLUSIONS: The combination of biweekly fluorouracil/leucovorin and imatinib 600 mg daily given in a week-on/week-off schedule was feasible and safe. Nausea and fluid retention represented the DLTs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Digestório/tratamento farmacológico , Proteínas Proto-Oncogênicas c-sis/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Mesilato de Imatinib , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos
12.
J Pharmacol Toxicol Methods ; 56(1): 23-7, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17395497

RESUMO

INTRODUCTION: PKC412 has proven activity in the treatment of acute myelogenous leukemia (AML). The drug is extensively metabolized, and recently it was shown that its metabolites have differing efficacies against malignant cells. Therefore, we established a new isocratic HPLC method, which sensitively detects PKC412 and five of its metabolites. METHOD: Quantification was performed using N-phenyl-1-naphtylamine as an internal standard. We could demonstrate linearity in a range from 10 to 10,000 ng/ml PKC412 with an intra-day variability of less than 7.5% and an inter-day-variability of less than 11%. RESULTS: The assay was used to monitor plasma samples from patients with AML treated within a clinical trial. Here we could demonstrate the ability of the assay to detect five metabolites of PKC412 and describe the application of the assay for drug monitoring in clinical situations. CONCLUSION: The assay described here will enable a discriminative analysis of PKC412 and its metabolites in human plasma samples. First clinical application of the assay suggests different rates of metabolism of the individual metabolites of PKC412 with e.g. accumulation of CGP52421 epimer 2 even after cessation of therapy. Since it is assumed that different metabolites of PKC412 have a very individual mode of actions, determination of PKC412 and its metabolites within clinical studies of the drug will be important.


Assuntos
Antineoplásicos/sangue , Estaurosporina/análogos & derivados , Doença Aguda , Cromatografia Líquida de Alta Pressão , Humanos , Leucemia Mieloide/tratamento farmacológico , Estaurosporina/sangue
14.
Artigo em Inglês | MEDLINE | ID: mdl-15113551

RESUMO

A highly sensitive and time-reduced HPLC assay for the quantitative analysis of busulfan in plasma and aqueous samples is described. The assay is based on a precolumn derivatization of busulfan to 1,4-diiodobutane and UV-detection of iodide ions generated by a postcolumn photochemical dissociation of the derivative. The extraction and derivatization were carried out in a one-pot reaction without any solid phase extraction and is therefore suitable for high throughput analysis. Quantification was performed by using 1,5-pentanediol-bis-(methanesulfonate), a homologue of busulfan, as an internal standard. Linearity was demonstrated for concentrations from 50 to 10,000ng/ml. The limit of detection was found at 10ng/ml. Precision is indicated by an intra-day variety of 2.81% and by an inter-day variety of 6.61% for aqueous samples, 2.93 and 5.76% for plasma samples, respectively. The recovery of busulfan in plasma was more than 95%. No coelution with metabolites of busulfan or other drugs used in cancer therapy was found. The method was generated for measurements of busulfan in aqueous or plasma samples and applied in therapeutic drug monitoring of busulfan.


Assuntos
Bussulfano/análise , Cromatografia Líquida de Alta Pressão/métodos , Fotólise , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrofotometria Ultravioleta
15.
Ann Hematol ; 83(6): 401-2, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-14673623

RESUMO

Imatinib mesylate (STI571) is a very effective treatment option for Ph(+) chronic myeloid leukemia (CML) in chronic phase. Secondary treatment failures have mostly been observed in patients with advanced stages of disease. We report the case of a patient who unexpectedly experienced blast crisis of the central nervous system although having achieved complete cytogenetic remission in the bone marrow. The levels of STI571 and its metabolite N-desmethyl STI were 40-fold lower in the cerebral spine fluid than in plasma. The risk of CNS disease has to be kept in mind when patients with CML in chronic phase who are at an increased risk for blastic transformation are treated with imatinib mesylate.


Assuntos
Antineoplásicos/líquido cefalorraquidiano , Crise Blástica/genética , Medula Óssea/patologia , Sistema Nervoso Central/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Piperazinas/líquido cefalorraquidiano , Pirimidinas/líquido cefalorraquidiano , Antineoplásicos/administração & dosagem , Benzamidas , Feminino , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/líquido cefalorraquidiano , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Indução de Remissão
16.
Cancer Chemother Pharmacol ; 53(4): 313-23, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-14658008

RESUMO

Despite the remarkable clinical response rates to imatinib in the treatment of bcr-abl leukemic patients, pharmacokinetic data on this relatively novel substance are needed to improve our understanding of the emergence of resistance, the interindividual variations of clinical response and the clinical and biologic relevance of its main metabolite N-desmethyl-imatinib. We present here pharmacokinetic data obtained with a newly designed HPLC approach in 97 patients with chronic myeloid leukemia or acute lymphatic leukemia (ALL) under treatment with imatinib that allowed us to calculate the AUC (39.5 microg.h/ml for an oral dose of 400 mg daily), the t(1/2) (18.2 h) and the peak concentration (1.92 micro/ml for an oral dose of 400 mg daily) of imatinib in plasma. In a subgroup of patients, the same parameters were analyzed for N-desmethyl-imatinib. We also provide data on the imatinib concentration in the cerebrospinal fluid (CSF) of ALL patients and demonstrate that oral administration of imatinib resulted only in a marginal flux across the blood-brain barrier. Finally, in an in vitro setting, we determined cellular concentrations of imatinib in HL-60 cells and showed an over-proportional uptake both in RPMI medium and in human plasma. Using an arithmetical approach combining all parameters obtained in imatinib-treated patients, we finally provide a conclusive approximation of basic pharmacokinetic data for both imatinib and its main metabolite N-desmethyl-imatinib.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Piperazinas/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Pirimidinas/farmacocinética , Administração Oral , Idoso , Benzamidas , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Células HL-60 , Meia-Vida , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Taxa de Depuração Metabólica , Piperazinas/sangue , Piperazinas/líquido cefalorraquidiano , Piperazinas/urina , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirimidinas/sangue , Pirimidinas/líquido cefalorraquidiano , Pirimidinas/urina
17.
Cancer Chemother Pharmacol ; 53(1): 61-7, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12955471

RESUMO

BACKGROUND: Clinical trials evaluating idarubicin (IDA) in acute myeloid leukemia, multiple myeloma and non-Hodgkin's lymphoma (NHL) have provided some evidence for an increased myelotoxicity of IDA compared to other anthracyclines. IDA is known to be less sensitive towards multidrug resistance mediated by P-glycoprotein (P-gp). This phenotype is a major impediment to successful antineoplastic treatment, but P-gp is also expressed on hematopoietic stem cells (HSC). METHODS: We investigated the pharmacokinetics of IDA and etoposide (ETO) in seven previously untreated patients with aggressive NHL. The patients received a CHOP-derived protocol (CIVEP) in which doxorubicin (DOX) was substituted by IDA 11-16 mg/m(2) and ETO 3 x 100 mg/m(2) was added. Furthermore, we evaluated in vitro the impact of P-gp expression on the cytotoxicity of DOX and IDA in cells from three parental chemosensitive leukemia and lymphoma cell lines (HL60, U937, CCRF) and their resistant sublines, as well as in CD34-positive HSC. RESULTS: The peak plasma levels (C(max)), terminal elimination half-life (t(1/2)) and area under the concentration curve (AUC) both for IDA and for ETO did not differ from published data. In cell line models the numbers of viable cells in a P-gp-expressing resistant CCRF-VCR100 subline were significantly more reduced by IDA ( P<0.001), but there was no difference in the cytotoxicities of IDA and DOX in chemosensitive CCRF cells and in the (non-P-gp-expressing) resistant U937 and HL60 sublines. Cytotoxicity against HSC was more pronounced after incubation with IDA than after treatment with DOX ( P=0.014), even when a tenfold higher concentration of DOX than of IDA was used. The addition of cyclosporin A increased the cytotoxic effect of DOX but not that of IDA in HSC. CONCLUSIONS: The pharmacokinetics of IDA and its main metabolite idarubicinol in CHOP-derived protocols were not different from data obtained with other combinations or monotherapy. The increased myelotoxicity of IDA may be a consequence of P-gp expression in CD34-positive HSC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Medula Óssea/efeitos dos fármacos , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/sangue , Etoposídeo/farmacologia , Meia-Vida , Humanos , Idarubicina/administração & dosagem , Idarubicina/efeitos adversos , Idarubicina/sangue , Idarubicina/farmacologia , Linfoma não Hodgkin/sangue , Pessoa de Meia-Idade , Células Tumorais Cultivadas
18.
Clin Cancer Res ; 9(13): 4674-81, 2003 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-14581336

RESUMO

PURPOSE: In patients with acute leukemias, a lymphoid phenotype, the presence of a Philadelphia chromosome (Ph), and inadequate central nervous system (CNS)-directed prophylactic therapy are risk factors for CNS involvement. Imatinib mesylate has promising single-agent antileukemic activity in patients with advanced Ph(+) acute leukemias. It was the aim of this analysis to determine the incidence of, and risk factors associated with, meningeal leukemia during imatinib monotherapy. STUDY DESIGN: We analyzed 107 consecutive patients with relapsed or refractory Ph(+) acute lymphoid leukemia (ALL; n = 65) or chronic myeloid leukemia blast crisis (n = 42) who were enrolled in successive Phase II trials of single-agent imatinib and who did not receive routine prophylactic intrathecal chemotherapy. RESULTS: CNS leukemia developed in 13 of 107 patients (12%) and was associated primarily with a lymphoid or bilineage phenotype (12 of 78; 15%) and with imatinib refractory Ph(+) ALL (5 of 19; 26%). Meningeal leukemia did not occur among patients who received prior prophylactic cranial irradiation. The median survival with combined CNS and systemic disease was 108 days (range, 58-141), with no patient surviving long term. In contrast, two of three patients with exclusively meningeal leukemia achieved prolonged molecular remissions with intrathecal chemotherapy, cranial irradiation, and continued imatinib. CONCLUSIONS: Patients with Ph(+) ALL are at considerable risk of meningeal leukemia during imatinib monotherapy and should routinely receive CNS prophylaxis. Although the prognosis with combined meningeal and systemic relapse is dismal, patients with an isolated meningeal relapse may still achieve sustained remissions. The optimal type of CNS-directed treatment and the extent of protection afforded by prophylactic cranial irradiation remain to be defined.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia/diagnóstico , Piperazinas/farmacologia , Pirimidinas/farmacologia , Adolescente , Adulto , Idoso , Antineoplásicos/farmacologia , Benzamidas , Neoplasias do Sistema Nervoso Central/secundário , Neoplasias do Sistema Nervoso Central/terapia , Cromatografia Líquida de Alta Pressão , Ensaios Clínicos como Assunto , Análise Mutacional de DNA , Feminino , Humanos , Mesilato de Imatinib , Leucemia/terapia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Fenótipo , Piperazinas/sangue , Piperazinas/líquido cefalorraquidiano , Prognóstico , Pirimidinas/sangue , Pirimidinas/líquido cefalorraquidiano , Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
19.
Blood ; 102(3): 820-6, 2003 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-12676781

RESUMO

A regimen of busulfan and cyclophosphamide is standard therapy before transplantation of allogeneic hematopoietic stem cells in patients with chronic myelogenous leukemia (CML) or myelodysplastic syndrome (MDS). The clinical trial reported here was undertaken to test the hypothesis that fludarabine can replace cyclophosphamide in this regimen and facilitate donor engraftment with reduced toxicity. The conditioning regimen consisted of 30 mg/m2 intravenous fludarabine daily from day -9 to day -6, and oral busulfan given at 1 mg/kg 4 times a day every 6 hours from day -5 to day -2, with doses adjusted to target plasma levels of 900 +/- 100 ng/mL at steady state. Cyclosporine and methotrexate were used for prophylaxis for graft-versus-host disease. Enrolled were 42 patients with high-risk CML (n = 4) or MDS (n = 38). The median patient age was 52 years (range, 12-65 years). Mobilized blood stem cells were obtained from HLA-compatible siblings (n = 16) or unrelated donors (n = 26). Engraftment was achieved in all patients, and the day-100 regimen-related mortality was 7%. With a median follow-up of 18 months (range, 13-27 months), the probabilities of overall survival, disease-free survival, and nonrelapse mortality were 42.4%, 34.9%, and 24%, respectively. These data indicate that the combination of fludarabine and targeted busulfan is sufficiently immunosuppressive to facilitate engraftment of blood stem cells from HLA-matched siblings and unrelated donors. Based on these encouraging results, further studies of fludarabine and targeted busulfan are warranted in standard-risk patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano/administração & dosagem , Transplante de Células-Tronco de Sangue Periférico/métodos , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Vidarabina/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Bussulfano/farmacocinética , Criança , Feminino , Seguimentos , Sobrevivência de Enxerto , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Recidiva , Análise de Sobrevida , Transplante Homólogo/imunologia , Vidarabina/farmacocinética , Vidarabina/toxicidade
20.
Cancer Chemother Pharmacol ; 51(3): 266-70, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12655447

RESUMO

PURPOSE: Gemcitabine (2',2'-difluorodeoxycytidine) is a cytotoxic agent with a low toxicity profile and proven activity against a number of solid tumors. It is not known whether gemcitabine is safe to administer to patients with kidney failure, and if dose adjustment is necessary. We determined the tolerability and pharmacokinetics of gemcitabine and its noncytotoxic metabolite 2',2'-difluorodeoxyuridine (dFdU) in a patient with end-stage renal disease on maintenance hemodialysis therapy. PATIENT AND METHODS: A 64-year-old patient with pancreatic cancer and end-stage renal disease received two cycles of gemcitabine at a standard dose of 1000 mg/m(2) given as a 30-min infusion on days 1 and 10. A regular 3.5-h hemodialysis treatment was performed 24 h after each infusion. Plasma and dialysate concentrations of gemcitabine and dFdU were determined by HPLC. The tolerability of gemcitabine treatment was assessed by clinical and laboratory parameters. RESULTS: For gemcitabine, the maximal plasma concentration, terminal half-life (t(1/2)) and area under the concentration-time curve (AUC) were similar to those reported for patients with normal renal function. In contrast, end-stage renal disease resulted in a five- to tenfold prolongation of terminal half-life and a distinct increase in the AUC of plasma dFdU in this patient. Plasma dFdU was effectively eliminated by hemodialysis treatment. Both cycles of gemcitabine were tolerated well with no unexpected side effects observed. CONCLUSIONS: Gemcitabine treatment in end-stage renal disease with intermittent standard hemodialysis treatment is safe and well tolerated. The pharmacokinetic data suggest that dose adjustment of gemcitabine should be avoided to ensure its full cytotoxic activity, and that hemodialysis treatment should be initiated 6-12 h after its administration to minimize the potential side effects of the metabolite dFdU.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Falência Renal Crônica/complicações , Neoplasias Pancreáticas/tratamento farmacológico , Diálise Renal , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Gencitabina
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