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1.
Nat Commun ; 11(1): 4659, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938936

RESUMO

The αvß6 integrin plays a key role in the activation of transforming growth factor-ß (TGFß), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvß6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvß6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFß signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvß6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvß6, induces prolonged inhibition of TGFß signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.


Assuntos
Butiratos/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Integrinas/antagonistas & inibidores , Naftiridinas/farmacologia , Pirazóis/farmacologia , Pirrolidinas/farmacologia , Administração por Inalação , Animais , Antígenos de Neoplasias/metabolismo , Bleomicina/toxicidade , Butiratos/administração & dosagem , Butiratos/metabolismo , Butiratos/farmacocinética , Colágeno/metabolismo , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/patologia , Integrinas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Naftiridinas/administração & dosagem , Naftiridinas/metabolismo , Naftiridinas/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/metabolismo , Pirrolidinas/farmacocinética , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Tomografia Computadorizada de Emissão de Fóton Único , Fator de Crescimento Transformador beta/metabolismo , Pesquisa Médica Translacional
2.
Clin Immunol ; 218: 108517, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32585295

RESUMO

Approximately 15% of patients with coronavirus disease 2019 (COVID-19) experience severe disease, and 5% progress to critical stage that can result in rapid death. No vaccines or antiviral treatments have yet proven effective against COVID-19. Patients with severe COVID-19 experience elevated plasma levels of pro-inflammatory cytokines, which can result in cytokine storm, followed by massive immune cell infiltration into the lungs leading to alveolar damage, decreased lung function, and rapid progression to death. As many of the elevated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these pathways with ruxolitinib has the potential to mitigate the COVID-19-associated cytokine storm and reduce mortality. This is supported by preclinical and clinical data from other diseases with hyperinflammatory states, where ruxolitinib has been shown to reduce cytokine levels and improve outcomes. The urgent need for treatments for patients with severe disease support expedited investigation of ruxolitinib for patients with COVID-19.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas/antagonistas & inibidores , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Síndrome Respiratória Aguda Grave/prevenção & controle , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Betacoronavirus/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Citocinas/genética , Citocinas/imunologia , Cálculos da Dosagem de Medicamento , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/genética , Janus Quinase 1/imunologia , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Janus Quinase 2/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/farmacocinética , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos
3.
J Environ Sci Health B ; 55(5): 477-483, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32449480

RESUMO

Pyraoxystrobin is a novel strobilurin fungicide that is widely used on many crops. The high log Kow of pyraoxystrobin implies that it tends to accumulate in aquatic organisms. This study optimized the sorbents of QuEChERS (quick, easy, cheap, effective, rugged, and safe) using 13C-labelled pyraoxystrobin as the internal standard (IS). It has been established a QuEChERS-LC-MS/MS IS method to study the bioconcentration and elimination of pyraoxystrobin in zebrafish (Danio rerio). The results indicated that the method had satisfactory linearity between 0.234 and 15 µg L-1 (R2 = 0.9996). The limits of detection (LOD) and quantification (LOQ) for pyraoxystrobin were 0.01 and 0.03 µg L-1, respectively. The LOQs of the method for water and zebrafish were 0.05 µg L-1 and 0.01 mg/kg, respectively. The mean recovery of pyraoxystrobin in zebrafish and water at fortification levels of 0.01-0.3 mg kg-1 and 0.05-1.5 µg L-1 ranged from 98.31 to 105.61% and 101.87 to 108.48%, respectively, with a % RSD (relative standard deviation) of 0.94-3.57%. The bioconcentration has been evaluated. The bioconcentration factors for pyraoxystrobin in zebrafish were 1,792 and 3,505 after exposure to 0.5 µg L-1 for 168 h and 0.05 µg L-1 for 216 h, respectively. The half-life of pyraoxystrobin in zebrafish was 9.0-9.5 d.


Assuntos
Acrilatos/análise , Acrilatos/farmacocinética , Fracionamento Químico/métodos , Pirazóis/análise , Pirazóis/farmacocinética , Peixe-Zebra , Acrilatos/toxicidade , Animais , Bioacumulação , Cromatografia Líquida , Ecotoxicologia/métodos , Fungicidas Industriais/análise , Fungicidas Industriais/farmacocinética , Fungicidas Industriais/toxicidade , Meia-Vida , Limite de Detecção , Pirazóis/toxicidade , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos , Testes de Toxicidade Aguda , Poluentes Químicos da Água/análise
4.
Artigo em Inglês | MEDLINE | ID: mdl-32278292

RESUMO

Repotrectinib, a next-generation ROS1/TRK/ALK tyrosine kinase inhibitor, overcomes resistance due to acquired solvent-front mutations involving ROS1, NTRK1-3, and ALK. A bioanalytical assay for quantification of repotrectinib in mouse plasma and seven tissue-related matrices (brain, liver, spleen, kidney, small intestinal tissue, small intestinal content, and testis homogenates) was developed and validated using liquid chromatography with tandem mass spectrometric detection in a high-throughput 96-well format. Protein precipitation was performed by adding acetonitrile, also containing the internal standard axitinib, to 10-µl samples for all matrices. Chromatographic separation of analytes was done on an ACQUITY UPLC® BEH C18 column by gradient elution using ammonium hydroxide in water and methanol. Compounds were monitored with positive electrospray ionization using a triple quadruple mass spectrometer in selected reaction monitoring mode. The method was successfully validated in the 1-1000 ng/ml calibration range. Precisions (intra- and interday) were in the range of 1.3-8.7% and accuracies were in between 90.5% and 107.3% for all levels in all matrices. The developed method was successfully applied to investigate the plasma pharmacokinetics and tissue accumulation of repotrectinib in wild-type mice.


Assuntos
Compostos Macrocíclicos/sangue , Compostos Macrocíclicos/farmacocinética , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/sangue , Pirazóis/farmacocinética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Animais , Axitinibe/química , Axitinibe/normas , Bioensaio , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Limite de Detecção , Compostos Macrocíclicos/administração & dosagem , Camundongos , Plasma/química , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirazóis/administração & dosagem , Receptor trkA/antagonistas & inibidores , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Distribuição Tecidual
5.
J Zoo Wildl Med ; 51(1): 53-58, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32212546

RESUMO

Mavacoxib is a selective cyclooxygenase-2 nonsteroidal anti-inflammatory drug that has been used for management of osteoarthritis and other inflammatory conditions in dogs. The main advantage of mavacoxib over other nonsteroidal anti-inflammatory drugs is its longer plasma half-life, leading to decreased dosing frequency. This study determined the pharmacokinetics of mavacoxib in Caribbean flamingos (Phoenicopterus ruber ruber) after a single-dose oral administration of 6 mg/kg (n = 6). Plasma mavacoxib concentrations were determined using liquid chromatography with mass spectrometry, and pharmacokinetic analysis was performed using noncompartmental methods. Mean peak plasma concentration (Cmax) was (mean; range) 2.97 (2.19--4.06) µg/ml; mean time to peak plasma concentration (Tmax) was 18.68 (4.00-48.00) hr; mean area under the curve (AUC) was 455 (292-637) hr * µg/ml; and mean terminal half-life (T1/2) was 74.47 (49.57-161.43) hr. Based on the results of this study, mavacoxib dosed at 6 mg/kg orally in Caribbean flamingos reaches plasma concentrations above the therapeutic concentration established for dogs, but further studies are needed to determine appropriate dosing recommendations in flamingos.


Assuntos
Animais de Zoológico/metabolismo , Anti-Inflamatórios não Esteroides/farmacocinética , Aves/metabolismo , Pirazóis/farmacocinética , Administração Oral , Animais , Feminino , Masculino
6.
Expert Opin Pharmacother ; 21(8): 863-870, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32124650

RESUMO

INTRODUCTION: Treatment of unresectable or metastatic urothelial carcinoma (UC) has historically relied upon platinum-based chemotherapy and, more recently, immune checkpoint inhibitors. When tumors progress despite those therapies, remaining effective options are limited. AREAS COVERED: In this review, the authors review the advancement in genomic targets in UC, most notably fibroblast growth factor receptor (FGFR). FGFR has been identified as a target in UC as it is commonly genomically altered (activating mutations or fusions), and may be enriched in UC subtypes that are relatively resistant to immune checkpoint blockade. Erdafitinib, a potent and selective inhibitor of FGFRs, represents the first targeted therapy approved for the treatment of UC by virtue of a confirmed response rate of 40% in an open-label, single-armed phase II trial in molecularly selected tumors. The authors provide their expert opinion of its approval and place it in the context of the current and forthcoming treatment strategies for metastatic UC. EXPERT OPINION: The approval of erdafitinib provides clinicians with an important new treatment option for patients with metastatic UC and projects forward into an era of enhanced molecular precision in identifying effective therapies in UC.


Assuntos
Antineoplásicos/uso terapêutico , Pirazóis/uso terapêutico , Quinoxalinas/uso terapêutico , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Ensaios Clínicos Fase II como Assunto , Humanos , Terapia de Alvo Molecular , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Quinoxalinas/farmacocinética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Resultado do Tratamento , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
7.
Respir Res ; 21(1): 75, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32216814

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvß6) integrin inhibitor, in participants with IPF. METHODS: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvß6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. RESULTS: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. CONCLUSIONS: This study demonstrated engagement of the αvß6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. TRIAL REGISTRATION: clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.


Assuntos
Butiratos/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Integrinas/antagonistas & inibidores , Naftiridinas/uso terapêutico , Pirazóis/uso terapêutico , Pirrolidinas/uso terapêutico , Volume de Ventilação Pulmonar/efeitos dos fármacos , Administração por Inalação , Idoso , Antígenos de Neoplasias , Teorema de Bayes , Butiratos/administração & dosagem , Butiratos/farmacocinética , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Masculino , Naftiridinas/administração & dosagem , Naftiridinas/farmacocinética , Nebulizadores e Vaporizadores , Tomografia por Emissão de Pósitrons , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinética , Resultado do Tratamento
9.
J Med Chem ; 63(5): 2620-2637, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32081010

RESUMO

The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3, which was optimized at the 2- and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Administração Oral , Animais , Descoberta de Drogas , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/farmacocinética , Humanos , Masculino , Simulação de Acoplamento Molecular , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Ratos Sprague-Dawley
10.
Drug Metab Pharmacokinet ; 35(1): 151-159, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32007354

RESUMO

BACKGROUND: The anticoagulant actions of oral direct factor Xa (FXa) inhibitors can be inferred from their observed plasma concentrations; however, the steady-state pharmacokinetics (PK) of different FXa inhibitors have not been compared in clinically. METHODS: The sensitivity of the rivaroxaban, apixaban, and edoxaban in the STA-Liquid Anti-FXa assay were compared, and the anti-FXa plasma concentrations were measured for PK assessments. Nonlinear mixed-effects modeling was used to assess population PK in 329 patients with nonvalvular atrial fibrillation or venous thromboembolism. Patients were followed up for an average of 3.6 years. RESULTS: Sensitivity was similar among the three drugs in this assay, which could directly compare plasma concentrations instead of anti-FXa activities. Overall exposure was greatest in 5 mg BID apixaban relative to other drugs (p < 0.001). The geometric mean AUC for the 0 to 24-h interval was 4550 ng h/mL for apixaban, 2710 ng h/mL for 15 mg QD rivaroxaban, and 1290 ng h/mL for 60 mg QD edoxaban. The PKs of 2.5 mg BID apixaban or 15 mg QD rivaroxaban were associated with hemorrhagic events. CONCLUSIONS: Apixaban was associated with greater exposure, higher trough concentrations in plasma compared with rivaroxaban or edoxaban. Furthermore, a higher plasma concentration may partially predict hemorrhagic events.


Assuntos
Anticoagulantes/farmacocinética , Inibidores do Fator Xa/farmacocinética , Fator Xa/metabolismo , Pirazóis/farmacocinética , Piridinas/farmacocinética , Piridonas/farmacocinética , Rivaroxabana/farmacocinética , Tiazóis/farmacocinética , Idoso , Anticoagulantes/sangue , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/metabolismo , Testes de Coagulação Sanguínea , Cromatografia Líquida , Inibidores do Fator Xa/sangue , Feminino , Humanos , Masculino , Estudos Prospectivos , Pirazóis/sangue , Piridinas/sangue , Piridonas/sangue , Rivaroxabana/sangue , Espectrometria de Massas em Tandem , Tiazóis/sangue , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/metabolismo
11.
Xenobiotica ; 50(8): 967-979, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32003293

RESUMO

1. Darolutamide is a novel selective androgen receptor antagonist consisting of two pharmacologically equipotent diastereoisomers. The absorption, distribution, metabolism and excretion properties of darolutamide in rats are reported.2. Non- or [14C]-labelled darolutamide, its diastereoisomers and major metabolite were studied in intact and bile duct-cannulated rats (oral and intravenous administration), and rat hepatocytes.3. Darolutamide was quickly (1 h to reach maximum plasma concentration) and completely absorbed after oral administration. Absolute bioavailability was high. Keto-darolutamide was the most abundant metabolite in rat hepatocytes and the only major one in plasma. Interconversion between diastereoisomers was observed.4. After oral administration, radioactivity distributed widely and homogeneously. Penetration into brain was low (brain/blood ratio = 0.079). Elimination was rapid from most tissues. Excretion occurred rapidly, and routes were similar irrespective of administration routes. Complete mass balance was reached by 168 h post-dose. Most radioactivity (61-64%) was excreted in faeces, while relevant amounts (30-33%) were also excreted into urine. The main clearance routes were metabolism via oxidative reactions and glucuronidation. After intravenous administration, a relevant extent of the dose (20%) underwent extrabiliary excretion as darolutamide.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacocinética , Pirazóis/farmacocinética , Administração Oral , Animais , Bile/metabolismo , Disponibilidade Biológica , Líquidos Corporais , Fezes , Absorção Intestinal , Ratos , Distribuição Tecidual
12.
Drug Res (Stuttg) ; 70(2-03): 101-106, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31931548

RESUMO

Larotrectinib, is an orally active novel small molecule approved for the treatment of solid tumors in pediatrics and adult patients. It acts by inhibiting tropomyosin receptor kinase. In this paper, we report the development and validation of a high-performance liquid chromatography (HPLC) method for the quantitation of larotrectinib in mice plasma as per the FDA regulatory guideline. Plasma samples processing was accomplished through simple protein precipitation using acetonitrile enriched with internal standard (IS, enasidenib). The chromatographic analysis was performed using a gradient mobile phase comprising 10 mM ammonium acetate and acetonitrile at a flow-rate of 0.8 mL/min on an X-Terra Phenyl column. The UV detection wave length was set at λmax 262 nm. Larotrectinib and the IS eluted at 3.85 and 6.60 min, respectively with a total run time of 8.0 min. The calibration curve was linear over a concentration range of 0.20-5.00 µg/mL (r2=≥0.992). The intra- and inter-day precision and accuracy results were within the acceptable limits. Results of stability studies indicated that larotrectinib was stable on bench-top, in auto-sampler, up to three freeze/thaw cycles and long-term storage at -80°C. The validated HPLC method was successfully applied to a pharmacokinetic study in mice.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Inibidores de Proteínas Quinases/análise , Pirazóis/análise , Pirimidinas/análise , Animais , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Masculino , Camundongos , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Reprodutibilidade dos Testes , Temperatura
13.
Eur J Clin Pharmacol ; 76(2): 185-197, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31919558

RESUMO

PURPOSE: The present studies assessed the drug-drug interaction of molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, with iron and calcium supplements, which are common medications in patients with anaemia due to chronic kidney disease (CKD). METHODS: Forty-two healthy men received molidustat alone (fasted or fed) or combined with oral iron(II) or calcium(II), given immediately before or between 4 h before and 1 h after molidustat in three randomized, open-label, crossover studies (12-15 participants per study). Molidustat AUC and Cmax were assessed as the main pharmacokinetic parameters, and endogenous erythropoietin (EPO) was measured to evaluate pharmacodynamics. RESULTS: Depending on prandial state, concomitant intake of iron(II) reduced molidustat AUC and Cmax by 50-75% and 46-84%, respectively, and EPO AUC(0-24) and Cmax by 31-44% and 36-48%, respectively. The influence of iron(II) declined with increasing the time interval to the intake of molidustat, with reductions in molidustat AUC and Cmax of 9% and 10%, respectively, when iron(II) intake occurred 4 h before molidustat. Accordingly, effects on endogenous EPO were less pronounced with increased time separation between oral iron(II) and molidustat intake. Calcium(II) reduced molidustat AUC and Cmax by 15% and 47%, respectively, without influence on EPO response. All treatments were well tolerated. CONCLUSIONS: In contrast to concomitant oral intake of calcium, the effect of oral iron supplements on molidustat pharmacokinetics and pharmacodynamics should be considered, and the two agents should be administered with an appropriate time separation.


Assuntos
Cálcio/administração & dosagem , Ferro/administração & dosagem , Pirazóis/administração & dosagem , Triazóis/administração & dosagem , Administração Oral , Adulto , Anemia/tratamento farmacológico , Área Sob a Curva , Cálcio/farmacologia , Estudos Cross-Over , Suplementos Nutricionais , Esquema de Medicação , Interações Medicamentosas , Eritropoetina/metabolismo , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Ferro/farmacologia , Masculino , Pessoa de Meia-Idade , Pirazóis/farmacocinética , Pirazóis/farmacologia , Fatores de Tempo , Triazóis/farmacocinética , Triazóis/farmacologia , Adulto Jovem
14.
Carbohydr Polym ; 229: 115476, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826488

RESUMO

The objective of present study is to explore whether polysaccharide could be a crystal growth inhibitor in poorly soluble antitumor drug Ibrutinib (IBR) formulation. In this work, small molecular ligands (amino or organic acids) in co-amorphous system (CAS) were preliminarily screened. A polysaccharide, microcrystalline cellulose (MCC) was selected to stabilize amorphous drug and enhance pharmacokinetic properties. Fourier-transform infrared, Raman, and X-ray photoelectron spectroscopy confirmed the ionic interaction of the ternary IBR formulation. Moreover, the biosafety of the ternary formulation was the same as that of IBR while the in vitro performance advantage of the ternary formulation was converted into higher bioavailability in vivo experiments. Overall, MCC as an effective crystal growth inhibitor in the novel ternary IBR formulation is a promising approach to improve the dissolution rate of crystalline drugs and the stability of amorphous drugs, as well as providing a theoretical basis for clinical applications.


Assuntos
Celulose/química , Pirazóis/química , Pirimidinas/química , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Fenômenos Químicos , Cristalização , Composição de Medicamentos , Humanos , Masculino , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos
15.
Biomed Chromatogr ; 34(1): e4703, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31629393

RESUMO

Ibrutinib has an excellent effect in the treatment of mantle cell lymphoma so it has attracted much attention. A novel ibrutinib nanocrystalline was exploited in our study to improve the bioavailability. A fast and reliable UPLC-MS/MS method was established for the accurate quantification of ibrutinib in rat plasma. The chromatographic separation was achieved by an Agilent zorbax SB-C18 rapid solution HD column (2.1 × 50 mm, 1.8 µm). The mobile phase consisted of deionized water (containing 10 mm ammonium acetate and 0.1% formic acid) and pure acetonitrile. Isocratic elution (water-acetonitrile 10:90, v/v) was adopted and the flow rate was 0.4 mL/min. Column temperature was set to 40°C. Vilazodone was used as the internal standard in this analytical method. Multiple reaction monitoring mode with positive electrospray ionization was selected to detect ibrutinib and vilazodone. Acetonitrile was used to precipitate protein to extract plasma samples. There was no endogenous interference for both ibrutinib and vilazodone and the linear range of this method was 1-2000 ng/mL. The recoveries were 98.4, 97.4 and 102.7% at low, medium and high concentrations. Accordingly, the matrix effect was 96.6, 111.1 and 99.6%. The pharmacokinetic difference between ibrutinib crude and a novel ibrutinib nanocrystalline in rats was investigated by this validated method successfully. The peak concentration and area under the concentration-time curve showed significant differences in gender and the bioavailability was improved after oral administration of ibrutinib nanocrystalline.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Nanopartículas/análise , Pirazóis/sangue , Pirimidinas/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Disponibilidade Biológica , Feminino , Limite de Detecção , Modelos Lineares , Masculino , Nanopartículas/química , Nanopartículas/metabolismo , Pirazóis/química , Pirazóis/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
16.
Biomed Chromatogr ; 34(2): e4721, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31656058

RESUMO

Teneligliptin is a recently developed dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of type 2 diabetes mellitus. To study simultaneous pharmacokinetics of teneligliptin and its major active metabolite, teneligliptin sulfoxide in human plasma, we developed and validated a LC-MS/MS method. The analytes were detected in the positive mode using multiple reaction monitoring (teneligliptin: m/z 427.2→243.1; teneligliptin-d8 : m/z 435.2→251.3; teneligliptin sulfoxide: m/z 443.2→68.2). The method demonstrated accuracy, precision, and linearity over the concentration range of 5 to 1000 ng/mL for teneligliptin and 2.5 to 500 ng/mL for teneligliptin sulfoxide. The developed method is the first fully validated method capable of simultaneous determination of teneligliptin and its active metabolite, teneligliptin sulfoxide in plasma. The suitability of the method was successfully demonstrated in terms of quantification of teneligliptin and teneligliptin sulfoxide pharmacokinetics in plasma samples collected from healthy volunteers. The measurement of plasma metabolite/parent ratio of teneligliptin was feasible by this method.


Assuntos
Cromatografia Líquida/métodos , Pirazóis/sangue , Espectrometria de Massas em Tandem/métodos , Tiazolidinas/sangue , Estabilidade de Medicamentos , Humanos , Limite de Detecção , Modelos Lineares , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacocinética , Reprodutibilidade dos Testes , Sulfóxidos/sangue , Sulfóxidos/química , Sulfóxidos/metabolismo , Sulfóxidos/farmacocinética , Tiazolidinas/química , Tiazolidinas/metabolismo , Tiazolidinas/farmacocinética
17.
Eur J Drug Metab Pharmacokinet ; 45(1): 101-111, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31673875

RESUMO

BACKGROUND AND OBJECTIVES: Erdafitinib, an oral selective pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The aim of this phase 1 study was to assess the pharmacokinetics and safety of erdafitinib in healthy participants when coadministered with fluconazole (moderate CYP2C9 and CYP3A inhibitor), and itraconazole (a strong CYP3A4 and P-glycoprotein inhibitor). The effect of CYP2C9 genotype variants (*1/*1, *1/*2, *1/*3) on the pharmacokinetics of erdafitinib was also investigated. METHODS: In this open-label, parallel-group, single-center study, eligible healthy adults were randomized by CYP2C9 genotype to receive Treatment A (single oral dose of erdafitinib 4 mg) on day 1, Treatment B (fluconazole 400 mg/day orally) on days 1-11, or Treatment C (itraconazole 200 mg/day orally) on days 1-11. Healthy adults randomized to Treatment B and C received a single oral 4-mg dose of erdafitinib on day 5. The pharmacokinetic parameters, including mean maximum plasma concentration (Cmax), area under the curve (AUC) from time 0 to 168 h (AUC168h), AUC from time 0 to the last quantifiable concentration (AUClast), and AUC from time 0 to infinity (AUC∞) were calculated from individual plasma concentration-time data using standard non-compartmental methods. RESULTS: Coadministration of erdafitinib with fluconazole increased Cmax of erdafitinib by approximately 21%, AUC168h by 38%, AUClast by 49%, and AUC∞ by 48% while coadministration with itraconazole resulted in no change in erdafitinib Cmax and increased AUC168h by 20%, AUClast by 33% and AUC∞ by 34%. Erdafitinib exposure was comparable between participants with CYP2C9 *1/*2 or *1/*3 and with wild-type CYP2C9 genotype. The ratio of total amount of erdafitinib excreted in the urine (inhibited to non-inhibited) was 1.09, the ratio of total amount of excreted metabolite M6 was 1.21, and the ratio of the metabolite to parent ratio in the urine was 1.11, when coadministration of erdafitinib with itraconazole was compared with single-dose erdafitinib. Treatment-emergent adverse events (TEAEs) were generally Grade 1 or 2 in severity; the most commonly reported TEAE was headache. No safety concerns were identified with single-dose erdafitinib when administered alone and in combination with fluconazole or itraconazole in healthy adults. CONCLUSION: Coadministration of fluconazole or itraconazole or other moderate/strong CYP2C9 or CYP3A4 inhibitors may increase exposure to erdafitinib in healthy adults and thus may warrant erdafitinib dose reduction or use of alternative concomitant medications with no or minimal CYP2C9 or CYP3A4 inhibition potential. TRIAL REGISTRATION: ClinicalTrials.gov identifier number: NCT03135106.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Interações Medicamentosas , Fluconazol/farmacologia , Itraconazol/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/farmacocinética , Quinoxalinas/farmacocinética , Adulto , Área Sob a Curva , Citocromo P-450 CYP2C9/genética , Combinação de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/urina , Pirazóis/efeitos adversos , Pirazóis/sangue , Pirazóis/urina , Quinoxalinas/efeitos adversos , Quinoxalinas/sangue , Quinoxalinas/urina , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores
18.
Fundam Clin Pharmacol ; 34(1): 109-119, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31411766

RESUMO

As an alternative to vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) are increasingly prescribed in combination with riociguat in the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). Pharmacokinetics of riociguat and DOACs are influenced by efflux transporters, such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). This work aimed to assess P-gp and BCRP-mediated drug-drug interactions of riociguat with DOACs using in vitro models. Bidirectional permeabilities of apixaban and rivaroxaban were investigated across MDCK-MDR1 and MDCK-BCRP models, in the absence and in the presence of increasing concentrations of riociguat (0.5-100 µm). Calculated efflux ratios were subsequently used to determine riociguat inhibition percentages and half maximal inhibitory concentration (IC50). P-gp-mediated efflux of apixaban and rivaroxaban was inhibited by 8% and 21%, respectively, in the presence of 100 µm riociguat. BCRP-mediated transport of apixaban and rivaroxaban was inhibited by 36% and 77%, respectively. IC50s of riociguat on MDCK-MDR1 and MDCK-BCRP models were higher than 100 µm for apixaban and higher than 100 µm and 46.5 µm for rivaroxaban, respectively. This work showed an in vitro inhibition of BCRP-mediated DOACs transport by riociguat. In vivo studies may be required to determine the clinical relevance of these transporter-mediated interactions.


Assuntos
Anticoagulantes/farmacocinética , Pirazóis/farmacologia , Pirazóis/farmacocinética , Piridonas/farmacocinética , Pirimidinas/farmacologia , Rivaroxabana/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Anticoagulantes/administração & dosagem , Transporte Biológico/efeitos dos fármacos , Cães , Interações Medicamentosas , Concentração Inibidora 50 , Células Madin Darby de Rim Canino , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Pirimidinas/administração & dosagem , Rivaroxabana/administração & dosagem
19.
Int J Cancer ; 146(6): 1631-1642, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31304590

RESUMO

Galunisertib (LY2157299), a promising small-molecule inhibitor of the transforming growth factor-beta (TGF-ß) receptor, is currently in mono- and combination therapy trials for various cancers including glioblastoma, hepatocellular carcinoma and breast cancer. Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters and the drug-metabolizing CYP3A complex in galunisertib pharmacokinetics. In vitro, galunisertib was vigorously transported by human ABCB1, and moderately by mouse Abcg2. Orally administered galunisertib (20 mg/kg) was very rapidly absorbed. Galunisertib brain-to-plasma ratios were increased by ~24-fold in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice compared to wild-type mice, but not in single Abcg2-/- mice, whereas galunisertib oral availability was not markedly affected. However, recovery of galunisertib in the small intestinal lumen was strongly reduced in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar boosted galunisertib brain accumulation in wild-type mice to equal the levels seen in Abcb1a/1b;Abcg2-/- mice. Oatp1a/1b deficiency did not alter oral galunisertib pharmacokinetics or liver distribution. Cyp3a-/- mice showed a 1.9-fold higher plasma AUC0-1 hr than wild-type mice, but this difference disappeared over 8 hr. Also, transgenic human CYP3A4 overexpression did not significantly alter oral galunisertib pharmacokinetics. Abcb1 thus markedly restricts galunisertib brain penetration and affects its intestinal disposition, possibly through biliary excretion. Elacridar coadministration could fully inhibit both processes, without causing acute toxicity. Moreover, mouse Cyp3a, but not human CYP3A4, may eliminate galunisertib at high plasma concentrations. These insights may help to guide the further clinical development and application of galunisertib.


Assuntos
Encéfalo/metabolismo , Pirazóis/farmacocinética , Quinolinas/farmacocinética , Fator de Crescimento Transformador beta/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Acridinas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Citocromo P-450 CYP3A/metabolismo , Cães , Feminino , Interações Ervas-Drogas , Humanos , Células Madin Darby de Rim Canino , Camundongos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Pirazóis/sangue , Pirazóis/farmacologia , Quinolinas/sangue , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Distribuição Tecidual
20.
Cancer Chemother Pharmacol ; 85(2): 391-399, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31875923

RESUMO

PURPOSE: Zanubrutinib (BGB-3111) is a potent Bruton's tyrosine kinase inhibitor with promising clinical activity in B-cell malignancies. Zanubrutinib was shown to be mainly metabolized through cytochrome P450 3A (CYP3A) in vitro. We evaluated the effect of steady-state rifampin (a strong CYP3A inducer) and steady-state itraconazole (a strong CYP3A inhibitor) on the pharmacokinetics (PK), safety, and tolerability of zanubrutinib in healthy Asian and non-Asian subjects. METHODS: In this open-label, two-part clinical study, 20 participants received a single oral dose of zanubrutinib (320 mg) and oral rifampin (600 mg) in Part A, and 18 participants received a single oral dose of zanubrutinib (20 mg) and oral itraconazole (200 mg) in Part B. Serial blood samples were collected after administration of zanubrutinib alone and zanubrutinib in combination with rifampin or itraconazole for the measurement of PK parameters. RESULTS: Coadministration with rifampin decreased AUC0-∞ of zanubrutinib by 13.5-fold and Cmax by 12.6-fold. Coadministration with itraconazole increased the AUC0-∞ of zanubrutinib by 3.8-fold and Cmax by 2.6-fold. The PK of zanubrutinib was consistent between Asian and non-Asian subjects, and  zanubrutinib was well tolerated in this study. CONCLUSIONS: These results confirm that zanubrutinib is primarily metabolized by CYP3A in humans. The PK of zanubrutinib was comparable between Asian and non-Asian subjects and, therefore, no dose modifications are necessary for zanubrutinib in these ethnic populations.


Assuntos
Indutores do Citocromo P-450 CYP3A/uso terapêutico , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Itraconazol/uso terapêutico , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Rifampina/uso terapêutico , Adolescente , Adulto , Idoso , Área Sob a Curva , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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