RESUMO
BACKGROUND: Ultra-performance Liquid Chromatography-tandem Mass Spectrometry (UPLC-MS/MS) is widely used for concentration detection of many Tyrosine Kinase Inhibitors (TKIs), including afatinib, crizotinib, and osimertinib. In order to analyze whether pralsetinib takes effect in Rearranged during Transfection (RET)-positive patients with central nervous system metastasis, we aimed to develop a method for the detection of pralsetinib concentrations in human plasma and Cerebrospinal Fluid (CSF) by UPLC-MS/MS. METHODS: The method was developed using the external standard method, and method validation included precision, accuracy, stability, extraction recovery, and matrix effect. Working solutions were all obtained based on stock solutions of pralsetinib of 1mg/mL. The plasma/CSF samples were precipitated by acetonitrile for protein precipitation and then separated on an ACQUITY UPLC HSS T3 column (2.1×100 mm, 1.8 µm) with a gradient elution using 0.1% formic acid (solution A) and acetonitrile (solution B) as mobile phases at a flow rate of 0.4 mL/min. The tandem mass spectrometry was performed by a triple quadrupole linear ion trap mass spectrometry system (QTRAPTM 6500+) with an electrospray ion (ESI) source and Analyst 1.7.2 data acquisition system. Data were collected in Multiple Reaction Monitoring (MRM) and positive ionization mode. RESULTS: A good linear relationship of pralsetinib in both plasma and CSF was successfully established, and the calibration ranges were found to be 1.0-64.0 µg/mL and 50.0ng/mL-12.8 µg/mL for pralsetinib in the plasma and CSF, respectively. Validation was performed, including calibration assessment, selectivity, precision, accuracy, matrix effect, extraction recovery, and stability, and all results have been found to be acceptable. The method has been successfully applied to pralsetinib concentration detection in a clinical sample, and the concentrations have been found to be 475 ng/mL and 61.55 µg/mL in the CSF and plasma, respectively. CONCLUSION: We have developed a quick and effective method for concentration detection in both plasma and CSF, and it can be applied for drug monitoring in clinical practice. The method can also provide a reference for further optimization.
Assuntos
Monitoramento de Medicamentos , Espectrometria de Massas em Tandem , Humanos , Monitoramento de Medicamentos/métodos , Cromatografia Líquida de Alta Pressão , Antineoplásicos/sangue , Antineoplásicos/líquido cefalorraquidiano , Pirróis/líquido cefalorraquidiano , Pirróis/sangue , Pirróis/química , Estrutura Molecular , Inibidores de Proteínas Quinases/líquido cefalorraquidiano , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/química , Espectrometria de Massa com Cromatografia Líquida , Pirazóis , Piridinas , PirimidinasRESUMO
Relapse at the central nervous system (CNS) in acute myeloid leukemia (AML) carries a dismal prognosis. Treatment options are limited to intrathecal therapy, high-dose cytarabine, high-dose methotrexate, and radiotherapy. Novel strategies are needed. Venetoclax has recently been approved by the FDA, in combination with hypomethylating agents or low-dose cytarabine, for elderly adults or patients ineligible for intensive chemotherapy affected by AML. However, little is known on its efficacy in patients with leptomeningeal involvement. Here, we present a case of a 52-year-old patient affected by AML relapsed at CNS after allogeneic bone marrow transplantation who was treated with venetoclax. We evaluated the concentration of the drug in cerebrospinal fluid (CSF) by HPLC MS/MS method on three different occasions to verify the penetration of the drug through the brain-blood barrier and we observed that the concentration in CSF was similar to the IC50 established in vitro.
Assuntos
Antineoplásicos/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Sulfonamidas/administração & dosagem , Antineoplásicos/líquido cefalorraquidiano , Barreira Hematoencefálica/metabolismo , Transplante de Medula Óssea/métodos , Compostos Bicíclicos Heterocíclicos com Pontes/líquido cefalorraquidiano , Cromatografia Líquida de Alta Pressão , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Neoplasias Meníngeas/patologia , Pessoa de Meia-Idade , Sulfonamidas/líquido cefalorraquidiano , Espectrometria de Massas em Tandem , Distribuição TecidualRESUMO
Treatment with small-molecule inhibitors, guided by precision medicine has improved patient outcomes in multiple cancer types. However, these compounds are often not effective against central nervous system (CNS) tumors. The failure of precision medicine approaches for CNS tumors is frequently attributed to the inability of these compounds to cross the blood-brain barrier (BBB), which impedes intratumoral target engagement. This is complicated by the fact that information on CNS penetration in CNS-tumor patients is still very limited. Herein, we evaluated cerebrospinal fluid (CSF) drug penetration, a well-established surrogate for CNS-penetration, in pediatric brain tumor patients. We analyzed 7 different oral anti-cancer drugs and their metabolites by high performance liquid chromatography mass spectrometry (HPLC-MS) in 42 CSF samples obtained via Ommaya reservoirs of 9 different patients. Moreover, we related the resulting data to commonly applied predictors of BBB-penetration including ABCB1 substrate-character, physicochemical properties and in silico algorithms. First, the measured CSF drug concentrations depicted good intra- and interpatient precision. Interestingly, ribociclib, vorinostat and imatinib showed high (> 10 nM), regorafenib and dasatinib moderate (1-10 nM) penetrance. In contrast, panobinostat und nintedanib were not detected. In addition, we identified active metabolites of imatinib and ribociclib. Comparison to well-established BBB-penetrance predictors confirmed low molecular weight, high proportion of free-drug and low ABCB1-mediated efflux as central factors. However, evaluation of diverse in silico algorithms showed poor correlation within our dataset. In summary, our study proves the feasibility of measuring CSF concentration via Ommaya reservoirs thus setting the ground for utilization of this method in future clinical trials. Moreover, we demonstrate CNS presence of certain small-molecule inhibitors and even active metabolites in CSF of CNS-tumor patients and provide a potential guidance for physicochemical and biological factors favoring CNS-penetration.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/líquido cefalorraquidiano , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Antineoplásicos/farmacocinética , Transporte Biológico , Criança , Feminino , Humanos , Masculino , Adulto JovemRESUMO
PURPOSE: Pexidartinib (PLX3397) is a colony-stimulating factor-1 receptor (CSF-1R) inhibitor under clinical evaluation for potential CNS tumor treatment. This study aims to evaluate plasma pharmacokinetic parameters and estimate CNS penetrance of pexidartinib in a non-human primate (NHP) cerebrospinal fluid (CSF) reservoir model. METHODS: Five male rhesus macaques, each with a previously implanted subcutaneous CSF ventricular reservoir and central venous lines, were used. NHPs received a single dose of 40 mg/kg pexidartinib (human equivalent dose of 800 mg/m2), administered orally as 200 mg tablets. Serial paired samples of blood and CSF were collected at 0-8, 24, 48, and 72 h. Pexidartinib concentrations were assayed by Integrated Analytical Solutions, Inc. (Berkeley, CA, USA) using HPLC/MS/MS. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. RESULTS: Samples from four NHPs were evaluable. Average (± SD) plasma PK parameters were as follows: Cmax = 16.50 (± 6.67) µg/mL; Tmax = 5.00 (± 2.58) h; AUClast = 250.25 (± 103.76) h*µg/mL; CL = 0.18 (± 0.10) L/h/kg. In CSF, pexidartinib was either quantifiable (n = 2), with Cmax values of 16.1 and 10.1 ng/mL achieved 2-4 h after plasma Tmax, or undetected at all time points (n = 2, LLOQCSF = 5 ng/mL). CONCLUSION: Pexidartinib was well-tolerated in NHPs, with no Grade 3 or Grade 4 toxicities. The CSF penetration of pexidartinib after single-dose oral administration to NHPs was limited.
Assuntos
Aminopiridinas , Barreira Hematoencefálica , Pirróis , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Aminopiridinas/administração & dosagem , Aminopiridinas/líquido cefalorraquidiano , Aminopiridinas/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/líquido cefalorraquidiano , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/fisiologia , Neoplasias Encefálicas/tratamento farmacológico , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Glioma/tratamento farmacológico , Macaca mulatta , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/administração & dosagem , Pirróis/líquido cefalorraquidiano , Pirróis/farmacocinéticaRESUMO
PURPOSE: Diffuse intrinsic pontine glioma (DIPG) is one of the deadliest forms of childhood cancers. To date, no effective treatment options have been developed. Recent drug screening studies identified the HDAC inhibitor panobinostat as an active agent against DIPG cells lines and animal models. To guide in the clinical development of panobinostat, we evaluated the CNS pharmacokinetics of panobinostat using CSF as a surrogate to CNS tissue penetration in a pre-clinical nonhuman primate (NHP) model after oral administration. METHODS: Panobinostat was administered orally to NHP (n = 3) at doses 1.0, 1.8, 2.4, and 3.0 mg/kg (human equivalent dose: 20, 36, 48, 60 mg/m2, respectively). The subjects served as their own controls where possible. Serial, paired CSF and plasma samples were collected for 0-48 h. Panobinostat was quantified via a validated uHPLC-MS/MS method. Pharmacokinetic (PK) parameters were calculated using non-compartmental methods. RESULTS: CSF penetration of panobinostat after systemic delivery was low, with levels detectable in only two subjects. CONCLUSION: The CSF penetration of panobinostat was low following oral administration in this pre-clinical NHP model predictive of human PK.
Assuntos
Antineoplásicos/farmacocinética , Neoplasias do Tronco Encefálico/tratamento farmacológico , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Panobinostat/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/líquido cefalorraquidiano , Neoplasias do Tronco Encefálico/líquido cefalorraquidiano , Neoplasias do Tronco Encefálico/patologia , Glioma Pontino Intrínseco Difuso/líquido cefalorraquidiano , Glioma Pontino Intrínseco Difuso/patologia , Humanos , Macaca mulatta , Masculino , Panobinostat/administração & dosagem , Panobinostat/líquido cefalorraquidiano , Distribuição TecidualRESUMO
BACKGROUND: Leptomeningeal metastases (LM) are much more frequent in patients of non-small lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFRTKI) shows promising efficacy for LM. OBJECTIVE: The aim of this study was to analyze the concentration of osimertinib and gene variation of circulating tumor DNA (ctDNA) in human plasma and cerebrospinal fluid (CSF). Furthermore, we explored whether ctDNA in CSF might be used as a biomarker to predict and monitor therapeutic responses. METHODS: The dynamic paired CSF and blood samples were collected from the NSCLC patient with LM acquired EGFR-TKI resistance. A method based on ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS/MS) was developed and validated for detecting osimertinib in CSF and plasma samples. Gene variations of ctDNA were tested by next-generation sequencing with a panel of 1021 genes. RESULTS: The concentrations of osimertinib in CSF were significantly lower than that in plasma (penetration rate was 1.47%). Mutations included mTOR, EGFR, CHECK1, ABCC11, and TP53 were explored in ctDNA from plasma and CSF samples. The detected mutation rate of CSF samples was higher than that of plasma samples (50% vs. 25%). Our data further revealed that the variations allele frequency (VAF) and molecular tumor burden index (mTBI) of ctDNA derived from CSF exhibited the negative correlation with efficacy of treatment. CONCLUSION: ctDNA from CSF might be a useful biomarker for monitoring the efficacy of treatment and an effective complement to nuclear magnetic resonance imaging (MRI) for LM.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , DNA Tumoral Circulante/sangue , Neoplasias Meníngeas/secundário , Mutação , Acrilamidas/sangue , Acrilamidas/líquido cefalorraquidiano , Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/líquido cefalorraquidiano , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Compostos de Anilina/sangue , Compostos de Anilina/líquido cefalorraquidiano , Compostos de Anilina/uso terapêutico , Antineoplásicos/sangue , Antineoplásicos/líquido cefalorraquidiano , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/líquido cefalorraquidiano , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , DNA Tumoral Circulante/genética , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/líquido cefalorraquidiano , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Meníngeas/sangue , Neoplasias Meníngeas/líquido cefalorraquidiano , Neoplasias Meníngeas/tratamento farmacológico , Pessoa de Meia-Idade , PrognósticoRESUMO
The central nervous system is a common site of relapse in patients receiving crizotinib, which is presumed to be associated with the low concentration of crizotinib in the cerebrospinal fluid (CSF). Our patient received surgical treatment for anaplastic lymphoma kinase-positive stage IIA lung adenocarcinoma. His cancer recurred with brain metastases and carcinomatous meningitis. We started whole-brain radiation therapy (WBRT) and subsequently administered crizotinib. The concentration of crizotinib on day 15 in the plasma was 158 ng/mL, and that in the spinal fluid was 4.32 ng/mL. WBRT may elevate the CSF/plasma crizotinib concentration ratio; clinicians may therefore consider performing WBRT prior to crizotinib initiation.
Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos/líquido cefalorraquidiano , Crizotinibe/líquido cefalorraquidiano , Neoplasias Pulmonares/tratamento farmacológico , Carcinomatose Meníngea/tratamento farmacológico , Adenocarcinoma de Pulmão/líquido cefalorraquidiano , Adenocarcinoma de Pulmão/radioterapia , Adenocarcinoma de Pulmão/secundário , Quinase do Linfoma Anaplásico/análise , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Terapia Combinada , Irradiação Craniana , Crizotinibe/uso terapêutico , Progressão da Doença , Evolução Fatal , Humanos , Neoplasias Pulmonares/líquido cefalorraquidiano , Masculino , Carcinomatose Meníngea/líquido cefalorraquidiano , Carcinomatose Meníngea/radioterapia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/líquido cefalorraquidiano , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
Chidamide is a new subtype-selective histone deacetylase inhibitor (HDACi), which has been approved for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in China. However, there are few studies about the application of chidamide in PTCL with central nervous system (CNS) involvement. It is essential to investigate the penetration of chidamide in the blood brain barrier (BBB). LC-MS methods were established firstly to determine the concentration of chidamide in rat plasma and CSF. Then five rats were anaesthetized and the plasma and CSF samples were collected at the time of 5, 15, 30, 60, 120, 180, 240, 360 and 480â¯min after being administered 1â¯mg/kg chidamide by intravenous injection, respectively. All samples were analyzed with the established LC-MS method by using the precursor/product transitions (m/z) of 391.1/265.1 for chidamide and 441.1/138.2 for internal standard (IS). The PK parameters were calculated after both of the concentrations of chidamide in plasma and CSF were determined. The penetration ratio of chidamide in BBB ranged from 0.19% to 0.67%. Result indicated chidamide could pass through the BBB, enter into the CNS and have the potential to be utilized in PTCL with CNS involvement.
Assuntos
Aminopiridinas/sangue , Aminopiridinas/líquido cefalorraquidiano , Antineoplásicos/sangue , Antineoplásicos/líquido cefalorraquidiano , Benzamidas/sangue , Benzamidas/líquido cefalorraquidiano , Inibidores de Histona Desacetilases/sangue , Inibidores de Histona Desacetilases/líquido cefalorraquidiano , Aminopiridinas/farmacocinética , Animais , Antineoplásicos/farmacocinética , Benzamidas/farmacocinética , Inibidores de Histona Desacetilases/farmacocinética , Masculino , Ratos Sprague-DawleyRESUMO
PURPOSE: Asparaginase (ASNase) is used to treat various hematological malignancies for its capacity to deplete asparagine (ASN) in serum and cerebrospinal fluid (CSF). Since the biological mechanisms underlying CSF asparagine depletion in humans are not yet fully elucidated, this study compared, for the first time, the pharmacological properties of three clinically used ASNase formulations in a rodent model. METHODS: Male Wistar rats were treated with E.coli-ASNase, PEG-ASNase, or ERW-ASNase at different doses. Serum and CSF amino-acid levels and ASNase activities were evaluated at 1 and 24 h after the intravenous administration of different ASNase doses. RESULTS: All the ASNase formulations showed higher activities in serum after 1 h than 24 h and completely deplete ASN. Mean ASNase activity in the CSF at 1 h was higher with ERW-ASNase compared to PEG-ASNase (36 ± 29 vs 8 ± 7 U/L, p < 0.037) and similar to E.coli-ASNase (21 ± 9 U/L, ns). ERW-ASNase and E.coli-ASNase at the highest doses were able to deplete ASN in the CSF after 1 h. This effect was transient and not evident at 24 h after treatment. CONCLUSIONS: Together with the ASN depletion in serum and CSF, a never before demonstrated transient penetration of ASNases into the CSF, more evident for non-pegylated formulations, was detected when the ASNases were administered at high dose.
Assuntos
Antineoplásicos/líquido cefalorraquidiano , Antineoplásicos/farmacocinética , Asparaginase/líquido cefalorraquidiano , Asparaginase/farmacocinética , Administração Intravenosa , Animais , Antineoplásicos/administração & dosagem , Asparaginase/administração & dosagem , Barreira Hematoencefálica/metabolismo , Dickeya chrysanthemi/enzimologia , Composição de Medicamentos , Escherichia coli/enzimologia , Meia-Vida , Masculino , Peso Molecular , Polietilenoglicóis/química , Ratos , Ratos WistarRESUMO
Avitinib (AC0010) is a mutant-selective epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), designed to be a targeted therapeutic agent for non-small cell lung cancer (NSCLC) patients harboring EGFR active and T790M resistant mutations. A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of Avitinib and its five metabolites (M1, M2, M4, M7, MII-6) in human cerebrospinal fluid (CSF). The samples were purified by protein precipitation and separated on a BEH C18 column (2.1×50mm, 1.7µm). Electrospray ionization (ESI) in positive ion mode and multiple reaction monitoring (MRM) were used to monitor the ion transitions at m/z 488/257, 474/403, 504/487, 434/377, 490/405, 476/391. The results indicated that the method had excellent sensitivity and specificity. The linear range covered from 0.05 to 50ng/mL for Avitinib, M1, M4, M7, and MII-6, and from 0.01 to 10ng/mL for M2. Intra-day and inter-day precisions (in terms of% RSD) were all <15% and the accuracies (in terms of% RE) were within the range of ±15%. The lower limit of quantification (LLOQ), matrix effect, extraction recovery, stability and dilution integrity were also validated and satisfied with the criteria of validation. Finally, the method was successfully applied to a blood-brain barrier (BBB) penetration rate research of NSCLC patients after an oral administration of Avitinib.
Assuntos
Antineoplásicos/líquido cefalorraquidiano , Barreira Hematoencefálica/metabolismo , Carcinoma Pulmonar de Células não Pequenas/líquido cefalorraquidiano , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/líquido cefalorraquidiano , Espectrometria de Massas em Tandem/métodos , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/fisiologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/líquido cefalorraquidiano , Inibidores Enzimáticos/metabolismo , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , MasculinoRESUMO
BACKGROUND: Systemic administration of oxaliplatin has no effect on the tumors in the central nervous system (CNS) due to the limited concentration of oxaliplatin in the cerebrospinal fluid (CSF), while it was clinically reported that oxaliplatin can induce acute encephalopathy. Currently, the impairment of neuronal functions in the CNS after systemic administration of oxaliplatin remains uninvestigated. METHODS: The von Frey test and the plantar test were performed to evaluate neuropathic pain behavior after a single intraperitoneal administration of oxaliplatin (4 mg/kg) in rats. Inductively coupled plasma-mass spectrometry, electrophysiologic recording, real-time quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, Western blot, immunohistochemistry, and small interfering RNA were applied to understand the mechanisms. RESULTS: Concentration of oxaliplatin in CSF showed a time-dependent increase after a single administration of oxaliplatin. Spinal application of oxaliplatin at the detected concentration (6.6 nM) significantly increased the field potentials in the dorsal horn, induced acute mechanical allodynia (n = 12 each) and thermal hyperalgesia (n = 12 each), and enhanced the evoked excitatory postsynaptic currents and spontaneous excitatory postsynaptic currents in the projection neurokinin 1 receptor-expressing lamina I to II neurons. The authors further found that oxaliplatin significantly increased the nuclear factor-κB p65 binding and histone H4 acetylation in cx3cl1 promoter region. Thus, the upregulated spinal CX3CL1 markedly mediated the induction of central sensitization and acute pain behavior after oxaliplatin administration. CONCLUSIONS: The findings of this study suggested that oxaliplatin in CSF may directly impair the normal function of central neurons and contribute to the rapid development of CNS-related side effects during chemotherapy. This provides novel targets to prevent oxaliplatin-induced acute painful neuropathy and encephalopathy.
Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/líquido cefalorraquidiano , Neuralgia/induzido quimicamente , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/líquido cefalorraquidiano , Animais , Quimiocina CX3CL1/metabolismo , Histonas/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Injeções Intraperitoneais , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxaliplatina , Medição da Dor , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores da Neurocinina-1/metabolismo , Fator de Transcrição RelA/metabolismoRESUMO
PURPOSE: Whole-brain radiation therapy (WBRT) is generally considered as an efficient strategy to improve blood-brain barrier (BBB) permeability by damaging BBB structure and is therefore, used as a promising pretreatment of chemotherapy. However, the impact of radiotherapy on leaky BBB is still controversial for the reason that BBB of metastatic brain tumor lesion had been breached by tumor metastasizing. Herein, we conducted a self-controlled study to evaluate the effect of WBRT on the permeability of BBB in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). METHOD: A prospective self-controlled research was performed. Radiation-naive NSCLC patients with BM were enrolled and treated with gefitinib for 2 weeks, and then concurrently combined with WBRT for 2 weeks. Plasma and cerebrospinal fluid (CSF) before and after WBRT were collected on day 15 and 29 after the initiation of gefitinib treatment. The concentrations of gefitinib in these samples were measured by HPLC. RESULTS: Three patients were enrolled and evaluated. The concentrations of gefitinib in plasma and CSF pre-WBRT were comparable to those of post-WBRT. Consequently, no significant change was noted in the CSF-to-plasma ratios of gefitinib before and after WBRT (2.79 ± 1.47 vs. 2.35 ± 1.74 %, p = 0.123). CONCLUSIONS: The WBRT may not affect the BBB permeability by determining the concentration of gefitinib in NSCLC patients with BM.
Assuntos
Antineoplásicos/farmacocinética , Barreira Hematoencefálica/efeitos da radiação , Neoplasias Encefálicas/radioterapia , Encéfalo/efeitos da radiação , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/farmacocinética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adulto , Idoso , Antineoplásicos/sangue , Antineoplásicos/líquido cefalorraquidiano , Antineoplásicos/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/efeitos da radiação , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/líquido cefalorraquidiano , Carcinoma Pulmonar de Células não Pequenas/secundário , Terapia Combinada , Receptores ErbB/antagonistas & inibidores , Feminino , Gefitinibe , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/efeitos da radiação , Projetos Piloto , Estudos Prospectivos , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/sangue , Quinazolinas/líquido cefalorraquidiano , Quinazolinas/uso terapêutico , Distribuição Tecidual/efeitos da radiaçãoRESUMO
Anti-BRAF agents, including vemurafenib, have modified the prognosis for patients with melanoma. However, a difference can still be observed between extracerebral and cerebral responses. The aim of this study was to investigate the diffusion of vemurafenib in cerebrospinal fluid (CSF) from patients treated for brain metastatic BRAF-V600 mutated melanoma. Six patients treated with vemurafenib 960 mg twice daily were included. These patients had undergone a lumbar puncture because of suspicions of leptomeningeal metastasis, along with simultaneous blood sampling to measure vemurafenib level. The concentrations of vemurafenib in the CSF and the plasma were measured by high-performance liquid chromatography. The mean plasma and CSF concentrations of vemurafenib were 53.4±26.2 and 0.47±0.37 mg/l, respectively. The mean ratio of the CSF : plasma concentration was 0.98±0.84%. No relationship was found between plasma and CSF concentrations (P=0.8). In conclusion, our preliminary results highlight for the first time a low CSF vemurafenib penetration rate associated with a large interindividual variability in patients treated for metastatic BRAF-V600 mutated melanoma and brain metastases. Further investigations with larger cohorts are required to study the relationship between CSF vemurafenib concentrations and cerebral response.
Assuntos
Antineoplásicos/líquido cefalorraquidiano , Indóis/líquido cefalorraquidiano , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Sulfonamidas/líquido cefalorraquidiano , Adulto , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/secundário , Cromatografia Líquida de Alta Pressão , Intervalo Livre de Doença , Feminino , Humanos , Indóis/sangue , Indóis/uso terapêutico , Masculino , Melanoma/líquido cefalorraquidiano , Melanoma/genética , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/patologia , Punção Espinal , Sulfonamidas/sangue , Sulfonamidas/uso terapêutico , Resultado do Tratamento , VemurafenibAssuntos
Antineoplásicos/líquido cefalorraquidiano , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/líquido cefalorraquidiano , Neoplasias Pulmonares/líquido cefalorraquidiano , Carcinomatose Meníngea/tratamento farmacológico , Pirazóis/líquido cefalorraquidiano , Piridinas/líquido cefalorraquidiano , Adulto , Quinase do Linfoma Anaplásico , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/secundário , Crizotinibe , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Carcinomatose Meníngea/secundário , Pessoa de Meia-Idade , Pirazóis/sangue , Pirazóis/uso terapêutico , Piridinas/sangue , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases/análiseRESUMO
INTRODUCTION: This phase 1 study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, cerebrospinal fluid (CSF) distribution, and preliminary clinical activity of the receptor tyrosine kinase inhibitor TAK-285. METHODS: Patients with advanced, histologically confirmed solid tumors and Eastern Cooperative Oncology Group performance status ≤2 received daily oral TAK-285; daily dose was escalated within defined cohorts until MTD and recommended phase 2 dose (RP2D) were determined. Eleven patients were enrolled into an RP2D cohort. Blood samples were collected from all cohorts; CSF was collected at pharmacokinetic steady-state from RP2D patients. Tumor responses were assessed every 8 weeks per Response Evaluation Criteria in Solid Tumors. RESULTS: Fifty-four patients were enrolled (median age 60; range, 35-76 years). The most common diagnoses were cancers of the colon (28 %), breast (17 %), and pancreas (9 %). Escalation cohorts evaluated doses from 50 mg daily to 500 mg twice daily; the MTD/RP2D was 400 mg twice daily. Dose-limiting toxicities included diarrhea, hypokalemia, and fatigue. Drug absorption was fast (median time of maximum concentration was 2-3 h), and mean half-life was 9 h. Steady-state average unbound CSF concentration (geometric mean 1.54 [range, 0.51-4.27] ng/mL; n = 5) at the RP2D was below the 50 % inhibitory concentration (9.3 ng/mL) for inhibition of tyrosine kinase activity in cells expressing recombinant HER2. Best response was stable disease (12 weeks of nonprogression) in 13 patients. CONCLUSIONS: TAK-285 was generally well tolerated at the RP2D. Distribution in human CSF was confirmed, but the free concentration of the drug was below that associated with biologically relevant target inhibition.
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Antineoplásicos/líquido cefalorraquidiano , Antineoplásicos/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/líquido cefalorraquidiano , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Receptores ErbB/antagonistas & inibidores , Hidroxibutiratos/líquido cefalorraquidiano , Hidroxibutiratos/farmacocinética , Neoplasias/líquido cefalorraquidiano , Neoplasias/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Demografia , Relação Dose-Resposta a Droga , Receptores ErbB/metabolismo , Feminino , Humanos , Hidroxibutiratos/administração & dosagem , Hidroxibutiratos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Receptor ErbB-2/metabolismo , Resultado do TratamentoRESUMO
The treatment of children with primary central nervous system (CNS) tumors continues to be a challenge despite recent advances in technology and diagnostics. In this overview, we describe our approach for identifying and evaluating active anticancer drugs through a process that enables rational translation from the lab to the clinic. The preclinical approach we discuss uses tumor subgroup-specific models of pediatric CNS tumors, cerebral microdialysis sampling of tumor extracellular fluid (tECF), and pharmacokinetic modeling and simulation to overcome challenges that currently hinder researchers in this field. This approach involves performing extensive systemic (plasma) and target site (CNS tumor) pharmacokinetic studies. Pharmacokinetic modeling and simulation of the data derived from these studies are then used to inform future decisions regarding drug administration, including dosage and schedule. Here, we also present how our approach was used to examine two FDA approved drugs, simvastatin and pemetrexed, as candidates for new therapies for pediatric CNS tumors. We determined that due to unfavorable pharmacokinetic characteristics and insufficient concentrations in tumor tissue in a mouse model of ependymoma, simvastatin would not be efficacious in further preclinical trials. In contrast to simvastatin, pemetrexed was advanced to preclinical efficacy studies after our studies determined that plasma exposures were similar to those in humans treated at similar tolerable dosages and adequate unbound concentrations were found in tumor tissue of medulloblastoma-bearing mice. Generally speaking, the high clinical failure rates for CNS drug candidates can be partially explained by the fact that therapies are often moved into clinical trials without extensive and rational preclinical studies to optimize the transition. Our approach addresses this limitation by using pharmacokinetic and pharmacodynamic modeling of data generated from appropriate in vivo models to support the rational testing and usage of innovative therapies in children with CNS tumors.
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Antineoplásicos/farmacocinética , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Simulação por Computador , Microdiálise , Modelos Biológicos , Fatores Etários , Animais , Antineoplásicos/sangue , Antineoplásicos/líquido cefalorraquidiano , Barreira Hematoencefálica/metabolismo , Neoplasias do Sistema Nervoso Central/metabolismo , Criança , Descoberta de Drogas , Humanos , PermeabilidadeRESUMO
BACKGROUND: Erlotinib shows large inter-patient pharmacokinetic variability, but the impact of early drug exposure and genetic variations on the clinical outcomes of erlotinib remains fully investigated. The primary objective of this study was to clarify the population pharmacokinetics/pharmacodynamics of erlotinib in Japanese patients with non-small cell lung cancer (NSCLC). The secondary objective was to identify genetic determinant(s) for the cerebrospinal fluid (CSF) permeability of erlotinib and its active metabolite OSI-420. METHODS: A total of 88 patients treated with erlotinib (150 mg/day) were enrolled, and CSF samples were available from 23 of these patients with leptomeningeal metastases. Plasma and CSF concentrations of erlotinib and OSI-420 were measured by high-performance liquid chromatography with UV detection. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modelling program NONMEM. Germline mutations including ABCB1 (1236C>T, 2677G>T/A, 3435C>T), ABCG2 (421C>A), and CYP3A5 (6986A>G) polymorphisms, as well as somatic EGFR activating mutations if available, were examined. Early exposure to erlotinib and its safety/efficacy relationship were evaluated. RESULTS: The apparent clearance of erlotinib and OSI-420 were significantly decreased by 24 and 35 % in patients with the ABCG2 421A allele, respectively (p < 0.001), while ABCB1 and CYP3A5 polymorphisms did not affect their apparent clearance. The ABCG2 421A allele was significantly associated with increased CSF penetration for both erlotinib and OSI-420 (p < 0.05). Furthermore, the incidence of grade ≥2 diarrhea was significantly higher in patients harboring this mutant allele (p = 0.035). A multivariate logistic regression model showed that erlotinib trough (C0) levels on day 8 were an independent risk factor for the development of grade ≥2 diarrhea (p = 0.037) and skin rash (p = 0.031). Interstitial lung disease (ILD)-like events occurred in 3 patients (3.4 %), and the median value of erlotinib C0 levels adjacent to these events was approximately 3 times higher than that in patients who did not develop ILD (3253 versus 1107 ng/mL; p = 0.014). The objective response rate in the EGFR wild-type group was marginally higher in patients achieving higher erlotinib C0 levels (≥1711 ng/mL) than that in patients having lower erlotinib C0 levels (38 versus 5 %; p = 0.058), whereas no greater response was observed in the higher group (67 %) versus the lower group (77 %) within EGFR mutation-positive patients (p = 0.62). CONCLUSIONS: ABCG2 can influence the apparent clearance of erlotinib and OSI-420, and their CSF permeabilities in patients with NSCLC. Our preliminary findings indicate that early exposure to erlotinib may be associated with the development of adverse events and that increased erlotinib exposure may be relevant to the antitumor effects in EGFR wild-type patients while having less of an impact on the tumor response in EGFR mutation-positive patients.
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Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/genética , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinas/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/sangue , Antineoplásicos/líquido cefalorraquidiano , Povo Asiático/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Cloridrato de Erlotinib , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Polimorfismo Genético , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/líquido cefalorraquidiano , Quinazolinas/sangue , Quinazolinas/líquido cefalorraquidianoRESUMO
The ability to deliver drug molecules effectively across the blood-brain barrier into the brain is important in the development of central nervous system (CNS) therapies. Cerebral microdialysis is the only existing technique for sampling molecules from the brain extracellular fluid (ECF; also termed interstitial fluid), the compartment to which the astrocytes and neurones are directly exposed. Plasma levels of drugs are often poor predictors of CNS activity. While cerebrospinal fluid (CSF) levels of drugs are often used as evidence of delivery of drug to brain, the CSF is a different compartment to the ECF. The continuous nature of microdialysis sampling of the ECF is ideal for pharmacokinetic (PK) studies, and can give valuable PK information of variations with time in drug concentrations of brain ECF versus plasma. The microdialysis technique needs careful calibration for relative recovery (extraction efficiency) of the drug if absolute quantification is required. Besides the drug, other molecules can be analysed in the microdialysates for information on downstream targets and/or energy metabolism in the brain. Cerebral microdialysis is an invasive technique, so is only useable in patients requiring neurocritical care, neurosurgery or brain biopsy. Application of results to wider patient populations, and to those with different pathologies or degrees of pathology, obviously demands caution. Nevertheless, microdialysis data can provide valuable guidelines for designing CNS therapies, and play an important role in small phase II clinical trials. In this review, we focus on the role of cerebral microdialysis in recent clinical studies of antimicrobial agents, drugs for tumour therapy, neuroprotective agents and anticonvulsants.
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Antibacterianos/farmacocinética , Antineoplásicos/farmacocinética , Fármacos do Sistema Nervoso Central/farmacocinética , Córtex Cerebral/metabolismo , Microdiálise , Animais , Antibacterianos/sangue , Antibacterianos/líquido cefalorraquidiano , Antineoplásicos/sangue , Antineoplásicos/líquido cefalorraquidiano , Barreira Hematoencefálica/metabolismo , Fármacos do Sistema Nervoso Central/sangue , Fármacos do Sistema Nervoso Central/líquido cefalorraquidiano , Ensaios Clínicos como Assunto , Descoberta de Drogas/métodos , Desenho de Equipamento , Humanos , Taxa de Depuração Metabólica , Microdiálise/instrumentaçãoRESUMO
BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have high response and disease control rates in patients with central nervous system (CNS) metastases. However there have been only a few case reports on the penetration of gefitinib into the cerebrospinal fluid (CSF). The aim of this study was to investigate the CSF concentration of gefitinib in Chinese patients with lung adenocarcinomas. METHODS: From March 2007 to December 2010, 22 patients were sequentially enrolled in this study at Peking Union Medical College Hospital (PUMCH). CSF and plasma samples were collected at the same time from each patient after at least 7 doses of gefitinib. The concentrations of gefitinib in the CSF and plasma were measured by high performance liquid chromatography coupled with tandem mass spectrometry. The clinical factors that may affect gefitinib penetration were analyzed. RESULTS: The mean plasma and CSF concentrations of gefitinib were 491.8 ± 184.2 ng/mL and 6.2 ± 4.6 ng/mL, respectively, and the mean ratio of CSF-plasma concentration was 1.3% ± 0.7%. There was a good correlation between CSF and plasma gefitinib concentrations (R = 0.556, P = .006). The presence of CNS metastases was associated with increased gefitinib CSF penetration (1.46% vs. 0.95%; P = .042). CONCLUSIONS: The concentration of gefitinib in CSF was low, and it was significantly related to the plasma gefitinib concentration. Because of the inadequate CNS drug exposure, patients in whom the extracranial lesions were well controlled may benefit from increasing gefitinib dose for the new intracranial lesions.
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Adenocarcinoma/tratamento farmacológico , Antineoplásicos/líquido cefalorraquidiano , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/líquido cefalorraquidiano , Adenocarcinoma de Pulmão , Adulto , Idoso , Barreira Hematoencefálica , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Cromatografia Líquida de Alta Pressão , Feminino , Gefitinibe , Humanos , Masculino , Pessoa de Meia-Idade , Quinazolinas/sangue , Espectrometria de Massas em TandemRESUMO
The purpose of this study is to assess how fludarabine (Fa) influences arabinosylcytosin's (Ara-C) mode of action. Plasma, cerebrospinal and urine samples were withdrawn from two study groups at specific time points and analyzed by HPLC. Group A was treated with Ara-C only whereas Group B was treated with Fa+Ara-C. The two study groups are all undergoing complete remission (CR). The Ara-C dose for Group A was 3g/m2 x 2, and the AUC(0-4) was 5.131 +/- 0.936. The Ara-C dose for Group B was 2g/m2 x 2, and the AUC(0-4) was 12.245 +/- 3.863. The AUC(0-4) for Group B is more than twice the AUC(0-4) for Group A, and these results indicate that Fa conduces a synergistic increase in the concentration and AUC of Ara-C in plasma and in cerebrospinal fluid. The pharmacokinetics between the different dose treatments was statistically different (P = 0.016). The differences in the ratios of C(Ara-u) to C(Ara-C), and in the Tmax between Groups A and B could indicate whether or not Ara-C combined with Fa. Although Group B demonstrates a higher AUC(0-4) with lower doses of Ara-C (2 g/m2 x 2), the adverse drug reaction (ADR) and bone inhibition were not more pronounced in Group B compared to Group A. These results are based on a limited number of case studies, hence, additional studies are necessary to support and prove this hypothesis.