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1.
Prague Med Rep ; 120(2-3): 52-63, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31586504

RESUMO

Tyrosine kinase inhibitors have recently become an essential tool in management of chronic myeloid leukaemia (CML). Dasatinib, a representative of those drugs, acts by inhibiting key proteins included in CML development, predominantly Bcr-Abl and Src. Its advantage is that it shows activity in many cases where other agents bring no improvement due to resistance. Pharmacokinetics of dasatinib has specific characteristics that may play an important role in achieving sufficient exposure in patients. Therefore, the key pharmacokinetic properties are summarized in this report. For example, dasatinib absorption is significantly influenced by gastric pH and its modulation can be a source of serious interactions, as well as simultaneous administration of drugs affecting cytochrome P450.


Assuntos
Dasatinibe/farmacocinética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Sistema Enzimático do Citocromo P-450 , Dasatinibe/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Ácido Gástrico , Humanos , Concentração de Íons de Hidrogênio , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico
2.
Crit Rev Oncol Hematol ; 141: 112-124, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31276964

RESUMO

Protein kinase inhibitors (PKI) are a growing class of anticancer agents. They are prescribed with flat doses, and their oral administration is associated with interindividual variability in exposure. Patients can be over- or underexposed, due to numerous factors. We reviewed key pharmacokinetic concepts and mechanisms by which PKIs prescription could be altered. Challenging situations that could lead to increased toxicity or to therapeutic failure are described and recommendation for clinicians are proposed. Finally, the interest of therapeutic drug monitoring and indications for its use in daily practice is discussed.


Assuntos
Padrões de Prática Médica/normas , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Área Sob a Curva , Biomarcadores Farmacológicos/análise , Relação Dose-Resposta a Droga , Interações de Medicamentos , Monitoramento de Medicamentos/métodos , Humanos , Inativação Metabólica/fisiologia , Farmacologia Clínica , Padrões de Prática Médica/estatística & dados numéricos , Inibidores de Proteínas Quinases/farmacologia , Distribuição Tecidual
3.
Chem Commun (Camb) ; 55(63): 9241-9250, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31328738

RESUMO

The field of chemical biology has introduced several approaches, typically using chemical probes, to measure the direct binding interaction of a small molecule with its biological target in cells. The use of these direct target engagement assays in pharmaceutical development can support mechanism of action hypothesis testing, rank ordering of compounds, and iterative improvements of chemical matter. This Feature Article highlights a newer application of these approaches: the quantification of target engagement in animal models to support late stage preclinical development and the nomination of a drug candidate to clinical trials. Broadly speaking, these efforts can be divided between compounds that covalently and reversibly interact with protein targets; recent examples for both categories are discussed for a range of targets, along with their limitations. New, promising technologies are also highlighted, in addition to the application of target engagement determination to new therapeutic modalities.


Assuntos
Modelos Animais , Preparações Farmacêuticas/metabolismo , Animais , Interações de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Preparações Farmacêuticas/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética
4.
Cancer Radiother ; 23(5): 432-438, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31331844

RESUMO

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (3 to 5% of all non-small cell lung cancers) carries a particularly high risk of central nervous system dissemination (60% to 90%). As the use of ALK inhibitors improves treatment outcomes over chemotherapy, the determent of central nervous system metastases has become an increasingly relevant therapeutic dilemma considering young age and possible extended overall survival. The goal of brain metastases management is to optimize both overall survival and quality of life, with the high priority of neurocognitive function preservation. Unfortunately in the first year on crizotinib, the pioneering ALK inhibitors, approximately one third of these patients fail in the central nervous system, which is explained by an inadequate central nervous system drug penetration through the blood-brain barrier. Central nervous system-directed radiotherapy represents the most important strategy to control intracranial disease burden and extend the survival benefit with crizotinib. The role of whole brain irradiation in the treatment of brain metastases diminishes, as this technique is associated with the risk of neurocognitive decline. Stereotactic radiotherapy represents an alternative technique that delivers ablative doses of ionizing radiation to the limited volume of oligometastatic brain disease, offering sparing of the adjacent brain parenchyma and reduced neurotoxicity. The next generation ALK inhibitors were designed to cross the blood-brain barrier more efficiently than crizotinib and achieve higher concentration in the cerebrospinal fluid, offering prominent ability to control central nervous system spread. In the phase III ALEX trial the intracranial control was significantly better with alectinib as compared to crizotinib and it translated into survival benefit. Other next generation ALK inhibitors (i.e. ceritinib, brigatinib, lorlatinib) also demonstrated promising activity in the central nervous system.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Pulmonares , Neoplasias Meníngeas/secundário , Proteínas de Neoplasias/antagonistas & inibidores , Quinase do Linfoma Anaplásico/análise , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/radioterapia , Carbazóis/farmacocinética , Carbazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Cisplatino/administração & dosagem , Ensaios Clínicos como Assunto , Terapia Combinada , Irradiação Craniana/efeitos adversos , Irradiação Craniana/métodos , Crizotinibe/farmacocinética , Crizotinibe/uso terapêutico , Gerenciamento Clínico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Meníngeas/enzimologia , Neoplasias Meníngeas/radioterapia , Camundongos , Terapia de Alvo Molecular , Proteínas de Neoplasias/análise , Transtornos Neurocognitivos/etiologia , Transtornos Neurocognitivos/prevenção & controle , Estudos Observacionais como Assunto , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Pemetrexede/administração & dosagem , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos
5.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1122-1123: 78-82, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31163324

RESUMO

Selitrectinib is a next generation tropomyosin receptor kinase (TRK) inhibitor developed to overcome acquired resistance to first generation TRK inhibitors. The drug is a cyclic analogue of larotrectinib. An existing bioanalytical assay for larotrectinib was therefore redesigned for selitrectinib. The assay used liquid chromatography-electrospray tandem mass spectrometry in positive selected reaction monitoring mode. Mouse plasma and tissue homogenates of brain, heart, kidney, liver, lung, small intestine, spleen, and testis were pretreated using acetonitrile protein precipitation with larotrectinib added as internal standard. Successful validation using current guidelines was obtained in the range 0.5-1000 ng/ml. Precision was within 5-12% and accuracy within 91-108% for all matrices investigated. The drug was stable in all matrices under the relevant storage conditions. Pharmacokinetics and tissue distribution of selitrectinib were monitored in a pilot study in mice demonstrating the applicability of the presented assay.


Assuntos
Compostos Aza/análise , Compostos Aza/farmacocinética , Cromatografia Líquida/métodos , Inibidores de Proteínas Quinases/análise , Inibidores de Proteínas Quinases/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Compostos Aza/química , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Inibidores de Proteínas Quinases/química , Reprodutibilidade dos Testes , Distribuição Tecidual
6.
Eur J Med Chem ; 176: 393-409, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31125894

RESUMO

Novel substituted purine isosters, were designed and synthesized as potential inhibitors of the Epidermal Growth Factor Receptor (EGFR). The compounds were rationally designed through bioisosteric replacement of the central quinazoline core of lapatinib, an approved drug that inhibits both EGFR and HER2, another important member of this family of receptors. The new target molecules were evaluated as inhibitors of receptor phosphorylation at the cellular level, for their direct inhibitory action on the intracellular receptor kinase domain and for their cytotoxicity against the non-small cell lung cancer cell line A549 and breast cancer HCC1954, cell lines which are associated with overexpression of EGFR and HER2, respectively. The most potent derivatives were further studied for their cellular uptake levels and in vivo pharmacokinetic properties. One compound (23) displayed a noteworthy pharmacokinetic profile, and higher intracellular accumulation in comparison to lapatinib in the A549 cells, possibly due to its higher lipophilicity. This lead compound (23) was assessed for its efficacy in an EGFR positive xenograft model, where it successfully inhibited tumor growth, with a similar efficacy with that of lapatinib and with minimal phenotypic toxicity.


Assuntos
Antineoplásicos/uso terapêutico , Lapatinib/análogos & derivados , Lapatinib/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Purinas/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Domínio Catalítico , Linhagem Celular Tumoral , Feminino , Humanos , Lapatinib/síntese química , Lapatinib/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Purinas/síntese química , Purinas/química , Purinas/farmacocinética , Receptor ErbB-2/química
7.
Eur J Med Chem ; 175: 247-268, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31121430

RESUMO

As a dual-specificity protein kinase, monopolar spindle 1 (Mps1) is one of the main kinases involved in kinetochore localization and the spindle assembly checkpoint (SAC). Cancer cells often display chromosomal instability, which is a consequence of disfunction of cell cycle checkpoints partially. Mps1 is overexpressed in multiple cancer types to face the pressure from aberrant chromosomes and centrosomes. Therefore, Mps1 is a potential targeting approach to cancer treatment. Several compounds targeting Mps1 have been developed and approved to begin clinical trials for advanced nonhaematologic malignancies treatments, including but not limited to triple negative breast cancer (TNBC) treatment. In this review, we will highlight typical Mps1 inhibitors developed during the last decade and provide a reference for more potential Mps1 inhibitors exploration in the future.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Desenho de Drogas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Fuso Acromático/efeitos dos fármacos , Antineoplásicos/farmacocinética , Proteínas de Ciclo Celular/química , Resistência a Medicamentos , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Conformação Proteica , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/química , Proteínas Tirosina Quinases/química , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/patologia
8.
Bioanalysis ; 11(8): 773-784, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30994009

RESUMO

Aim: BPI15086 is a potent, irreversible mutant-selective inhibitor of both EGFR (EGFR tyrosine kinase inhibitor) and the T790M resistance mutations tyrosine kinase. A simultaneous quantification method of BPI15086 and its main metabolite in human plasma using LC-MS/MS is documented and fully validated in this study. Methodology & results: Plasma samples were extracted and chromatographed on an Acquity ultra-high performance liquid chromatography BEH C18 column with a gradient elution. Detection was performed on a Sciex 5500 QTRAP® mass spectrometer using positive electrospray ionization. The results indicated that the method had excellent sensitivity and specificity. Conclusion: For the first time a sensitive and robust ultra-high performance liquid chromatography-MS/MS method was established and validated of BPI15086 in human plasma, this method was successfully applied in a first-in-human Phase I clinical trial studying the pharmacokinetics of the BPI15086 tablet in Chinese non-small-cell lung cancer patients.


Assuntos
Cromatografia Líquida/métodos , Plasma/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Espectrometria de Massas em Tandem/métodos , Humanos , Inibidores de Proteínas Quinases/farmacologia
9.
Pharmacol Res Perspect ; 7(2): e00470, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30906562

RESUMO

Nilotinib is a broad-based tyrosine kinase inhibitor with the highest affinity to inhibit Abelson (c-Abl) and discoidin domain receptors (DDR1/2). Preclinical evidence indicates that Nilotinib reduces the level of brain alpha-synuclein and attenuates inflammation in models of Parkinson's disease (PD). We previously showed that Nilotinib penetrates the blood-brain barrier (BBB) and potentially improves clinical outcomes in individuals with PD and dementia with Lewy bodies (DLB). We performed a physiologically based population pharmacokinetic/pharmacodynamic (popPK/PD) study to determine the effects of Nilotinib in a cohort of 75 PD participants. Participants were randomized (1:1:1:1:1) into five groups (n = 15) and received open-label random single dose (RSD) 150:200:300:400 mg Nilotinib vs placebo. Plasma and cerebrospinal fluid (CSF) were collected at 1, 2, 3, and 4 hours after Nilotinib administration. The results show that Nilotinib enters the brain in a dose-independent manner and 200 mg Nilotinib increases the level of 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), suggesting alteration to dopamine metabolism. Nilotinib significantly reduces plasma total alpha-synuclein and appears to reduce CSF oligomeric: total alpha-synuclein ratio. Furthermore, Nilotinib significantly increases the CSF level of triggering receptors on myeloid cells (TREM)-2, suggesting an anti-inflammatory effect. Taken together, 200 mg Nilotinib appears to be an optimal single dose that concurrently reduces inflammation and engages surrogate disease biomarkers, including dopamine metabolism and alpha-synuclein.


Assuntos
Encéfalo/metabolismo , Doença de Parkinson/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Encéfalo/efeitos dos fármacos , Estudos de Coortes , Dopamina/sangue , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Drogas em Investigação/administração & dosagem , Drogas em Investigação/análise , Drogas em Investigação/farmacocinética , Ácido Homovanílico/líquido cefalorraquidiano , Ácido Homovanílico/metabolismo , Humanos , Glicoproteínas de Membrana/líquido cefalorraquidiano , Pessoa de Meia-Idade , Doença de Parkinson/sangue , Placebos/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/líquido cefalorraquidiano , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/sangue , Pirimidinas/líquido cefalorraquidiano , Pirimidinas/farmacocinética , Receptores Imunológicos , alfa-Sinucleína/sangue , alfa-Sinucleína/metabolismo
10.
Cancer Sci ; 110(5): 1686-1694, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30815927

RESUMO

We evaluated the safety, efficacy, pharmacokinetics, pharmacodynamics and predictive biomarkers of tirabrutinib, a second-generation, enhanced-selectivity Bruton's tyrosine kinase inhibitor in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-cell NHL) and chronic lymphocytic leukemia (CLL). This was an open-label, multicenter, phase I study. Seventeen patients (male N = 8) with a median age of 70 years were enrolled in 4 dose cohorts (160 mg once daily [N = 3], 320 mg once daily [N = 3], 480 mg once daily [N = 4] and 300 mg twice daily [N = 7]); 4 patients had continued tirabrutinib administration as of 4 January 2018. The maximum tolerated dose was not reached. Pneumonitis (N = 1) was the dose-limiting toxicity for 300 mg twice daily. Common adverse events (AEs) were rash (35.3%) and vomiting (29.4%). Eight patients (47.1%) developed grade ≥3 AEs: neutropenia (23.5%), anemia (11.8%) and leukopenia (11.8%) were frequent. The overall response rate (≥PR) was 76.5% (13/17 patients), including 4 DLBCL patients with no CD79A/B or MYD88 mutations, and 1 CLL patient with a TP53 mutation, providing promising data for future developments. Of 16 patients with measurable lesions during the screening period, 12 showed ≥50% reductions in tumor diameter. In many patients, the tumor size decreased soon after beginning treatment. The maximum serum concentration for tirabrutinib was 611, 1220, 1280 and 886 ng/mL on Day 1 and 484, 971 1940, and 961 ng/mL on Day 28 for Cohorts 1-4, respectively. Tirabrutinib pharmacokinetics were linear, with little accumulation following multiple doses. Tirabrutinib was well tolerated and showed promising efficacy for B-cell NHL/CLL.


Assuntos
Imidazóis/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antígenos CD79/genética , Esquema de Medicação , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Japão , Leucemia Linfocítica Crônica de Células B/genética , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/genética , Recidiva Local de Neoplasia/genética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética
11.
Chem Pharm Bull (Tokyo) ; 67(3): 224-235, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828000

RESUMO

Mutant activin receptor-like kinase-2 (ALK2) was reported to be closely associated with the pathogenesis of fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG), and therefore presents an attractive target for therapeutic intervention. Through in silico virtual screenings and structure-activity relationship studies assisted by X-ray crystallographic analyses, a novel series of bis-heteroaryl pyrazole was identified as potent inhibitors of ALK2 (R206H). Derived from in silico hit compound RK-59638 (6a), compound 18p was identified as a potent inhibitor of ALK2 (R206H) with good aqueous solubility, liver microsomal stability, and oral bioavailability.


Assuntos
Receptores de Ativinas Tipo I/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Simulação por Computador , Cristalografia por Raios X , Meia-Vida , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Miosite Ossificante/enzimologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Espectroscopia de Prótons por Ressonância Magnética , Pirazóis/administração & dosagem , Pirazóis/química , Pirazóis/farmacocinética , Solubilidade , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 170: 112-125, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30878826

RESUMO

A series of 24 benzothiadiazine derivatives with structural novelty were designed, synthesized and biologically evaluated as PI3Kδ-selective inhibitors. As a consequence of the structure-activity relationship (SAR) study, compounds 63 and 71 were identified with single-digit nanomolar IC50 values against PI3Kδ and submicromolar GI50 values against human malignant B-cell line SU-DHL-6. Furthermore, chiral resolution of the key amine intermediate of these two compounds was performed to achieve corresponding enantiomers. In subsequent biological evaluation, S-63 (IC50: 4.6 nM) and S-71 (IC50: below 0.32 nM) demonstrated comparable and superior PI3Kδ inhibitory activity, respectively, to that of idelalisib. Additionally, both S-63 (GI50: 33.2 nM) and S-71 (GI50: 15.9 nM) exerted enhanced anti-proliferative activity against the SU-DHL-6 cell line than that of idelalisib. Moreover, both S-63 and S-71 exhibited excellent PI3Kδ selectivity. In the further in vivo pharmacokinetic (PK) study, S-63 displayed a good plasma exposure and an acceptable oral bioavailability of 29.2%. By virtue of its biological performance, S-63 merits further development as a potential therapeutic agent for battling B-cell-mediated malignancies.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzotiadiazinas/química , Benzotiadiazinas/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Linfoma de Células B/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Linfócitos B/patologia , Benzotiadiazinas/síntese química , Benzotiadiazinas/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Desenho de Drogas , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley
14.
Ther Drug Monit ; 41(2): 160-167, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30883509

RESUMO

Pharmacodynamic (PD) monitoring may complement routine pharmacokinetic monitoring of mTOR inhibitors (mTORis) in an attempt to better guide individualized sirolimus (SRL) or everolimus (EVR) treatment after organ transplantation. This review focuses on current knowledge about PD biomarkers for personalized mTORi therapies. Different strategies have already been used in the evaluation of the pharmacodynamics of SRL and EVR as a proxy for their effects on the immune response after transplantation. These include measuring p70S6K (70 kDa ribosomal protein S6 kinase) activity, p70S6K phosphorylation (P-p70S6K), or P-S6 protein expression. Compared with Western blot and ELISA, phosphoflow cytometry can detect phosphorylated proteins and differentiate activation-induced changes of signaling molecules inside the cell from unstimulated populations of identical cells in the same sample. Alternatively, in patients receiving a combined therapy, the other PD approach is to consider biomarkers such as NFAT residual expression for calcineurin inhibitors or to evaluate nonspecific effects of the drugs such as lymphocyte proliferation, interleukin synthesis, specific peripheral blood T regulatory subsets, or lymphocyte surface antigens, which have the advantage to reflect the overall immunosuppressive status achieved. Although limited, the available data on mTOR pathway biomarkers seem promising. Before clinical implementation, the analytical methodologies must be standardized and cross-validated, and the selected biomarkers will have to demonstrate their clinical utility for SRL or EVR dose individualization in multicenter clinical trials.


Assuntos
Monitoramento de Medicamentos/métodos , Everolimo/farmacocinética , Everolimo/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Sirolimo/farmacocinética , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Biomarcadores/metabolismo , Humanos , Inibidores de Proteínas Quinases/uso terapêutico
15.
Med Oncol ; 36(5): 39, 2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30919115

RESUMO

The aim of this study was to examine the association of lenvatinib-induced adverse events with the trough plasma concentration (C0) in Japanese patients with thyroid cancer. Patients received lenvatinib 24 mg as an initial dose, and sequential dose reductions were conducted based on the grade of each side effect. Assessment of adverse events, assay of lenvatinib C0, and analysis of clinical laboratory tests were performed at the same time of day and were retrospectively analyzed. There were no significant differences in lenvatinib C0 among grades of hypertension, proteinuria, hand-foot syndrome, and diarrhea. However, levels of aspartate transaminase, alanine transaminase, and total bilirubin were significantly higher in lenvatinib C0 quartile (Q) 4 (≥ 88 ng/mL) than in Q1 (< 42 ng/mL) and Q2-3 (42-88 ng/mL). Additionally, platelet counts were highest in the lowest Q1 group. The median dose of lenvatinib in patients with UGT1A1*6/*6 or *6/*28 (poor metabolizers [PMs]) was significantly lower than that in patients with UGT1A1*1/*1 (10 and 14 mg, respectively), whereas the median bilirubin levels were significant higher in UGT1A1 PMs (0.9 and 0.5 mg/dL, respectively). There were no significant differences in median lenvatinib C0 values between patients with UGT1A1*1/*1 and PMs (58.0 and 50.0 ng/mL, respectively). The threshold between the C0 and toxicity of lenvatinib may be more than 88 ng/mL. Therefore, the dose of lenvatinib could be controlled to maintain a lower C0 of less than 88 ng/mL. The target C0 for lenvatinib as the threshold between the C0 and optimal response may be in the range from 42 to 88 ng/mL; however, further studies are necessary.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/fisiopatologia , Feminino , Genótipo , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/sangue , Compostos de Fenilureia/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/administração & dosagem , Quinolinas/sangue , Quinolinas/farmacocinética , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/genética
16.
J Pharm Biomed Anal ; 168: 64-74, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30797103

RESUMO

In this study, a simple and sensitive quantitation method based on liquid chromatography combined with diode array detector and Q-Exactive-Orbitrap tandem mass spectrometry was developed for the determination of MK-8353 in rat plasma. The chromatographic separation was carried out on a Waters ACQUITY BEH C18 column by using water containing 1 mM ammonium acetate and acetonitrile containing 0.1% formic acid as mobile phase. The developed assay was linear (r > 0.999) over the concentration range of 1-1000 ng/mL. The selectivity, precision, accuracy, recovery, matrix effects and stability were all within the required limits. The validated assay has been further applied to the pharmacokinetic study of MK-8353 in rat after intravenous and oral administration, which revealed that MK-8353 showed low clearance and satisfactory bioavailability. More importantly, the metabolites of MK-8353 present in rat plasma, RLM, DLM and HLM were identified and profiled. Under the current conditions, a total of 10 metabolites were detected and their chemical structures were proposed in terms of the accurate masses and their fragment ions. Our results revealed that MK-8353 was metabolized mainly through dealkylation, demethylation, depropylation, oxygenation, sulfur oxidation and formation of lactam. Compared with animal species, no human-specific metabolite was found in HLM. This study provides overall in vitro and in vivo profiles of MK-8353, which is of great help in understanding its PK/PD profiles and in predicting human pharmacokinetic profiles.


Assuntos
Cromatografia Líquida/métodos , Indazóis/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/farmacocinética , Pirrolidinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Triazóis/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Cães , Feminino , Humanos , Indazóis/administração & dosagem , Indazóis/sangue , Masculino , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Piridinas/administração & dosagem , Piridinas/sangue , Pirrolidinas/administração & dosagem , Pirrolidinas/sangue , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Especificidade da Espécie , Triazóis/administração & dosagem , Triazóis/sangue
17.
Eur J Med Chem ; 166: 318-327, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30731400

RESUMO

Axl is a new promising molecular target for antineoplastic therapies. A series of quinolone antibiotic derivatives were designed and synthesized as new selective Axl inhibitors. One of the most promising compound 8i bound tightly to Axl with a Kd value of 1.1 nM, and inhibited its kinase activity with an IC50 value of 26 nM. The compound also significantly inhibited the phosphorylation of Axl and dose dependently inhibited cell invasion and migration in TGF-ß1 induced MDA-MD-231 breast cancer cells. In addition, 8i demonstrated reasonable pharmacokinetic properties and exhibited extraordinary target selectivity over 468 kinases except for Flt3 (IC50 = 50 nM)), with a S(10) and S(35) value of 0.022 and 0.42 at 1.0 µM, respectively. Compound 8i may serve as a new valuable lead compound for future anticancer drug discovery.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Quinolonas/química , Quinolonas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Antibacterianos/farmacocinética , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Masculino , Inibidores de Proteínas Quinases/farmacocinética , Quinolonas/farmacocinética , Ratos , Ratos Sprague-Dawley
18.
Cancer Sci ; 110(4): 1340-1351, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30724423

RESUMO

Capmatinib is a highly specific, potent and selective MET inhibitor. This was an open-label, multicenter, dose-escalation, phase I study conducted in Japanese patients with advanced solid tumors (not selected based on their MET status). The primary objective was to determine the maximum tolerated dose (MTD) and/or highest studied dose being safe. Secondary objectives included safety, pharmacokinetics and preliminary antitumor activity. Dose escalation was guided by a Bayesian Logistic Regression Model dependent on dose-limiting toxicities (DLT) in cycle 1. Of 44 adult Japanese patients with confirmed advanced solid tumors enrolled, 29 received capmatinib capsules (doses ranging from 100 mg once daily [q.d.] to 600 mg twice daily [b.i.d.]) and 15 received tablets (200 mg b.i.d. and 400 mg b.i.d.). DLT occurred in two patients: grade 2 suicidal ideation (600 mg b.i.d. capsule) and grade 3 depression (400 mg b.i.d. tablet). MTD was not reached. The highest studied dose determined to be safe as tablet was 400 mg b.i.d., whereas it is not yet determined for capsules. Most common adverse events suspected to be drug-related were increased blood creatinine, nausea, decreased appetite, vomiting and diarrhea. Following repeated daily dosing up to day 15 by q.d. or b.i.d. regimen using capsules, median time to reach maximum plasma drug concentration (Tmax ) was 1.0-4.0 hours; absorption was more rapid after dosing using tablets, with median Tmax of 1.0 hour on both days 1 and 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib.


Assuntos
Antineoplásicos/administração & dosagem , Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Triazinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Biomarcadores , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/metabolismo , Neoplasias/mortalidade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Análise de Sobrevida , Resultado do Tratamento , Triazinas/efeitos adversos , Triazinas/farmacocinética
19.
Eur J Pharmacol ; 850: 126-134, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30753868

RESUMO

Studies on the role of Rho-associated protein kinase (ROCK) in experimental pulmonary artery hypertension (PAH) relies mainly on the use of pharmacological inhibitors. However, interpreting these data is hampered by the lack of specificity of commonly utilized inhibitors. To fill this gap, we have selected and characterized a novel ROCK inhibitor, Compound 3, previously described in a patent. Inhibitory potency of Compound 3 against enzymatic activity of ROCK-1 and 2 (IC50 = 10 ±â€¯3.1 and 7.8 ±â€¯0.5 nM, respectively) was accompanied by a strong vasodilating effect in phenylephrine pre-contracted isolated rat pulmonary artery rings (IC50 = 51.7 ±â€¯9.1 nM) as well as in aortic rings (IC50 = 45.5 ±â€¯1.1 nM). Compound 3 showed a remarkable selectivity towards ROCK 1 and 2 when tested against a large panel (>400) of human kinases. A partial explanation for its selectivity is provided from docking simulations within ROCK-1. Pharmacokinetic studies showed that Compound 3 is suitable for a twice daily administration without significant accumulation upon repeated dosing. In rats with monocrotaline (MCT)-induced pulmonary hypertension, therapy with Compound 3, (1 and 3 mg/kg, s.c., b.i.d.), started 14 days after induction of the disease, attenuated right ventricle systolic pressure (RVSP) increase. Morphometric histological analysis showed that Compound 3, at both doses, counteracted MCT-induced medial thickening of lung distal arterioles with an effect comparable to macitentan (10 mg/kg, p.o., q.d.). Compound 3 is a potent and highly selective ROCK inhibitor that ameliorates hemodynamic parameters and counteracts pulmonary vascular remodeling in experimental PAH.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aorta/fisiopatologia , Antagonistas dos Receptores de Endotelina/farmacologia , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Simulação de Acoplamento Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Ratos , Distribuição Tecidual , Remodelação Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Quinases Associadas a rho/química , Quinases Associadas a rho/metabolismo
20.
Invest Ophthalmol Vis Sci ; 60(2): 624-633, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30735565

RESUMO

Purpose: The purpose of this study was to investigate the IOP-lowering effects of the ITRI-E-212, a new Rho-associated protein kinase (ROCK) inhibitor. ITRI-E-212 improved fluid outflow through the trabecular meshwork and reduced IOP with transient and mild conjunctival hyperemia. ITRI-E-212 can potentially be developed into new antiglaucoma agents. Methods: ITRI-E-212 was selected from more than 200 amino-isoquinoline structures because of its adequate solubility and drug-loading percentage in eye drops. ITRI-E-212 has less than 50% inhibitory concentration (IC50) against ROCK2. The in vitro kinase inhibition was evaluated using the ADP-Glo kinase assay. A comprehensive analysis of the kinase inhibitor selectivity of ITRI-E-212 was performed using the KINOMEscan methodology. The IOP-lowering effect and tolerability of ITRI-E-212 were investigated in normotensive and ocular hypertensive rabbits. The pharmacokinetics study was performed in vivo in the aqueous humor (AH), and hyperemia was assessed. Results: ITRI-E-212 showed high in vitro inhibitory activity against ROCK2 and high specificity against AGC kinases. The mean IOP-lowering effect of ITRI-E-212 in normotensive and ocular hypertensive models was 24.9% and 28.6%, respectively; 1% ITRI-E-212 produced notable reductions in IOP that were sustained for at least 6 hours after each dose once per day. Only transient, mild hyperemia was observed. The compound extracted from the AH reached 78.4% ROCK2 kinase inhibition at 1 hour after dose administration and was sustained for 4 hours. Conclusions: ITRI-E-212 is a novel and highly specific ROCK2 inhibitor with the ability to lower IOP in animal models. It has favorable pharmacokinetic and ocular tolerability profiles with only minimal conjunctival hyperemia.


Assuntos
Anti-Hipertensivos/administração & dosagem , Glaucoma/tratamento farmacológico , Hiperemia/induzido quimicamente , Pressão Intraocular/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Quinases Associadas a rho/antagonistas & inibidores , Administração Oftálmica , Animais , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacocinética , Humor Aquoso/metabolismo , Túnica Conjuntiva/irrigação sanguínea , Modelos Animais de Doenças , Pálpebras/irrigação sanguínea , Glaucoma/fisiopatologia , Hiperemia/epidemiologia , Incidência , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Isoquinolinas/farmacocinética , Masculino , Cadeias Leves de Miosina/metabolismo , Soluções Oftálmicas , Fosforilação , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Coelhos
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