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1.
Artigo em Inglês | MEDLINE | ID: mdl-32361632

RESUMO

Edoxaban is mainly enzymatically converted to a 4-carboxylic acid form (4CA-EDX) and an N-desmethyl form (ND-EDX) in humans. This study aimed to establish a simple liquid chromatography-tandem mass spectrometry method using core-shell octadecyl silica (ODS) microparticles for the simultaneous quantitation of edoxaban and its two major metabolites in human plasma. Analytes extracted from plasma specimens by a one-step deproteinization were separated using a 2.6-µm core-shell ODS microparticulate column and linear acetonitrile-ammonium acetate gradient elution at a flow rate of 0.25 mL/min with a run time of 7 min. The mass spectrometer was operated in the positive ion multiple reaction monitoring mode. Plasma samples collected from 20 patients with atrial fibrillation were analyzed by the present method. The chromatograms of drug-free human plasma had no interfering peaks. The calibration curves of edoxaban, 4CA-EDX, and ND-EDX were linear over the concentration ranges of 1.25-160, 0.47-60, and 0.12-15 ng/mL, respectively. Their pretreatment recoveries and matrix factors were 88.7-109.0% and 87.0-101.6%, respectively. The intra- and inter-day accuracy and imprecision values were 85.9-112.8% and within 13.3%, respectively. The plasma concentrations of edoxaban, 4CA-EDX, and ND-EDX in the patients had ranges of 17.8-102, 1.67-25.7, and 0.685-5.34 ng/mL, respectively. All the analytes were measurable within their calibration curves. In conclusion, this validated method for the simultaneous determination of edoxaban and its major metabolites was successfully applied to plasma specimens obtained from patients with atrial fibrillation.


Assuntos
Piridinas/sangue , Piridinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Tiazóis/sangue , Tiazóis/farmacocinética , Técnicas Biossensoriais , Coleta de Amostras Sanguíneas , Cromatografia Líquida de Alta Pressão , Humanos , Limite de Detecção , Metabolômica , Microesferas , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Dióxido de Silício/química
2.
J Thromb Haemost ; 18(6): 1320-1323, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32329231

RESUMO

BACKGROUND: Antiviral drugs are administered in patients with severe COVID-19 respiratory syndrome, including those treated with direct oral anticoagulants (DOACs). Concomitant administration of antiviral agents has the potential to increase their plasma concentration. A series of patients managed in the Cremona Thrombosis Center were admitted at Cremona Hospital for SARS-CoV-2 and started antiviral drugs without stopping DOAC therapy. DOAC plasma levels were measured in hospital and results compared with those recorded before hospitalization. METHODS: All consecutive patients on DOACs were candidates for administration of antiviral agents (lopinavir, ritonavir, or darunavir). Plasma samples for DOAC measurement were collected 2to 4 days after starting antiviral treatment, at 12 hours from the last dose intake in patients on dabigatran and apixaban, and at 24 hours in those on rivaroxaban and edoxaban. For each patient, C-trough DOAC level, expressed as ng/mL, was compared with the one measured before hospitalization. RESULTS: Of the 1039 patients hospitalized between February 22 and March 15, 2020 with COVID-19 pneumonia and candidates for antiviral therapy, 32 were on treatment with a DOAC. DOAC was stopped in 20 and continued in the remaining 12. On average, C-trough levels were 6.14 times higher during hospitalization than in the pre-hospitalization period. CONCLUSION: DOAC patients treated with antiviral drugs show an alarming increase in DOAC plasma levels. In order to prevent bleeding complications, we believe that physicians should consider withholding DOACs from patients with SARS-CoV-2 and replacing them with alternative parenteral antithrombotic strategies for as long as antiviral agents are deemed necessary and until discharge.


Assuntos
Antitrombinas/sangue , Antivirais/efeitos adversos , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Dabigatrana/sangue , Inibidores do Fator Xa/sangue , Pneumonia Viral/tratamento farmacológico , Pirazóis/sangue , Piridinas/sangue , Piridonas/sangue , Tiazóis/sangue , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/administração & dosagem , Antitrombinas/efeitos adversos , Antivirais/administração & dosagem , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Dabigatrana/administração & dosagem , Dabigatrana/efeitos adversos , Darunavir/efeitos adversos , Interações Medicamentosas , Monitoramento de Medicamentos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Itália , Lopinavir/efeitos adversos , Masculino , Pandemias , Segurança do Paciente , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Medição de Risco , Fatores de Risco , Ritonavir/efeitos adversos , Índice de Gravidade de Doença , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos
3.
Artigo em Inglês | MEDLINE | ID: mdl-32251991

RESUMO

Clinical studies are needed to clarify the use of direct oral anticoagulants (DOACs) in breastfeeding women. To support emerging clinical studies on investigating DOAC's transfer into breast milk, an ultra-high-performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for quantifying three DOACs - apixaban, edoxaban and rivaroxaban in human plasma and breast milk. Protein precipitation with methanol was performed for sample preparation. Chromatographic analysis was performed using a C18 column. The MS detection was performed in MRM mode. The method was validated in accordance with the European Guideline (EMA). The calibration range was 5-500 ng/mL in plasma and 5-250 ng/mL in breast milk. The within-batch and between-batch variability remained <9%. Recoveries ranged from 106.13% to 109.05% in plasma and from 93.40% to 107.91% in breast milk. The lot-to-lot matrix variability was within ±15% among a range of samples originating from many different subjects. All analytes were stable when stored for 24 h at room temperature, 7 days at 2-8 °C, and at least 5 weeks at -20 °C in both plasma and breast milk. The developed method fulfilled the EMA bioanalytical method validation guideline and was shown to be simple, fast, accurate and will now be used in a clinical trial evaluating the transfer of apixaban and rivaroxaban into human breast milk.


Assuntos
Anticoagulantes/sangue , Leite Humano/química , Pirazóis/sangue , Piridinas/sangue , Piridonas/sangue , Rivaroxabana/sangue , Tiazóis/sangue , Administração Oral , Anticoagulantes/administração & dosagem , Aleitamento Materno , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Lactação , Limite de Detecção , Estrutura Molecular , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Piridonas/administração & dosagem , Reprodutibilidade dos Testes , Rivaroxabana/administração & dosagem , Espectrometria de Massas em Tandem , Tiazóis/administração & dosagem
4.
PLoS One ; 15(2): e0228797, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32074133

RESUMO

(E)-N,N-dimethyl-4-oxo-4-(4-(pyridin-4-yl)phenyl)but-2-enamide hydrochloride (IMB-YH-4py5-2H) is a novel Protein Kinase B (PknB) inhibitor with potent activity against Mycobacterium tuberculosis strains. In the present study, a sensitive and specific liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine IMB-YH-4py5-2H in rat plasma. Sample pretreatment was achieved by liquid-liquid extraction with ethyl acetate, and separation was performed on an XTerra MS C18 column (2.1×50 mm, 3.5 µm) with gradient elution (methanol and 0.1% formic acid) at a flow rate of 0.3 mL/min. Detection was performed in multiple reaction monitoring (MRM) mode. Linear calibration curves were obtained over a concentration range of 1-100 ng/mL. The intra-day and inter-day precisions were lower than 8.46%, and the accuracies ranged from -8.71% to 12.36% at all quality control levels. The extraction recoveries were approximately 70%, and the matrix effects were negligible. All quality control samples were stable under different storage conditions. The validated method was successfully applied to a preclinical pharmacokinetic study in Sprague-Dawley rats. IMB-YH-4py5-2H demonstrated improved pharmacokinetic properties (higher exposure level) compared with its leading compound. IMB-YH-4py5-2H was also distributed throughout the lung pronouncedly, especially inside alveolar macrophages, indicating its effectiveness against lower respiratory infections.


Assuntos
Análise Química do Sangue/métodos , Cromatografia Líquida/métodos , Limite de Detecção , Piridinas/sangue , Piridinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Antituberculosos/sangue , Antituberculosos/isolamento & purificação , Antituberculosos/farmacocinética , Piridinas/isolamento & purificação , Ratos , Ratos Sprague-Dawley
5.
PLoS One ; 15(2): e0228822, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32032379

RESUMO

A novel LC-MS/MS method was developed for the quantification of the new cyclin dependent kinase inhibitors (CDKIs) palbociclib and ribociclib and the aromatase inhibitor letrozole used in combinatory regimen. The proposed method is appropriate to be applied in clinical practice due to the simple and fast sample preparation based on protein precipitation, the low amount of patient sample necessary for the analysis (10 µL) and the total run time of 6.5 min. It was fully validated according to FDA and EMA guidelines on bioanalytical method validation. The linearity was assessed (R2 within 0.9992-0.9983) over the concentration ranges of 0.3-250 ng/mL for palbociclib, 10-10000 ng/mL for ribociclib and 0.5-500 ng/mL for letrozole that properly cover the therapeutic plasma concentrations. A specific strategy was implemented to reduce the carryover phenomenon, formerly known for these CDKIs. This method was applied to quantify the Cmin of palbociclib, ribociclib and letrozole in plasma samples from patients enrolled in a clinical study. The same set of study samples was analysed twice in separate runs to assess the reproducibility of the method by means of the incurred samples reanalysis. The results corroborated the reliability of the analyte concentrations obtained with the bioanalytical method, already proved by the validation process. The percentage differences were always within ±10% for all the analytes and the R2 of the correlation graph between the two quantifications was equal to 0.9994.


Assuntos
Aminopiridinas/sangue , Cromatografia Líquida de Alta Pressão/métodos , Letrozol/sangue , Piperazinas/sangue , Purinas/sangue , Piridinas/sangue , Espectrometria de Massas em Tandem/métodos , Estabilidade de Medicamentos , Humanos , Reprodutibilidade dos Testes
6.
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
7.
Int J Pharm ; 578: 119043, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31962190

RESUMO

This study aimed to develop an evaluation approach for supersaturation by employing an in vitro bio-mimicking apparatus designed to predict in vivo performance. The Biphasic Gastrointestinal Simulator (BGIS) is composed of three chambers with absorption phases that represent the stomach, duodenum, and jejunum, respectively. The concentration of apatinib in each chamber was detected by fiber optical probes in situ. The dissolution data and the pharmacokinetic data were correlated by GastroplusTM. The precipitates were characterized by polarizing microscope, Scanning Electron Microscopy, Powder X-ray diffraction and Differential scanning calorimetry. According to the results, Vinylpyrrolidone-vinyl acetate copolymer (CoPVP) prolonged supersaturation by improving solubility and inhibiting crystallization, while Hydroxypropyl methylcellulose (HPMC) prolonged supersaturation by inhibiting crystallization alone. Furthermore, a predictive in vitro-in vivo correlation was established, which confirmed the anti-precipitation effect of CoPVP and HPMC on in vitro performance and in vivo behavior. In conclusion, CoPVP and HPMC increased and prolonged the supersaturation of apatinib, and then improved its bioavailability. Moreover, BGIS was demonstrated to be a significant approach for simulating in vivo conditions for in vitro-in vivo correlation in a supersaturation study. This study presents a promising approach for evaluating supersaturation, screening precipitation inhibitors in vitro, and predicting their performances in vivo.


Assuntos
Mucosa Gástrica/metabolismo , Derivados da Hipromelose , Absorção Intestinal , Povidona/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Duodeno , Derivados da Hipromelose/administração & dosagem , Derivados da Hipromelose/química , Derivados da Hipromelose/farmacocinética , Jejuno , Masculino , Camundongos Endogâmicos C57BL , Povidona/administração & dosagem , Povidona/química , Povidona/farmacocinética , Piridinas/administração & dosagem , Piridinas/sangue , Piridinas/química , Piridinas/farmacocinética , Estômago
8.
Artigo em Inglês | MEDLINE | ID: mdl-31931326

RESUMO

Cabozantinib is a novel multi-target tyrosine kinase inhibitor recently approved in metastatic renal cell carcinoma (mRCC) leading to frequent severe toxicities requiring empirical dose reduction. Therapeutic drug monitoring (TDM) could help to predict the risk for severe toxicities by quickly detecting overexposed patients followed by prospective adaptive dosing strategy. To achieve this goal, a simple and rapid assay to monitor cabozantinib plasma concentration was developed and validated. After a single precipitation step with 87% recovery, cabozantinib was assayed by liquid chromatography tandem mass spectrometry (electrospray ionization interface) over a 25-5000 ng/ml range covering usual plasma levels in clinical setting. For cabozantinib and cabozantinib 2H4 used as internal standard, quantification was performed using the m/z 502 â†’ m/z 323 and m/z 506 â†’ m/z 323 transitions, respectively. Analytical runtime was 5 min. Both inter-days and intra-day accuracy and precision were <15%. When tested in routine clinical practice in a subset of mRCC patients treated with standard 60 mg quaque die (QD) dosing, the method proved to be fully adapted and neither analytical interferences nor matrix effect was observed. Results showed that cabozantinib trough levels were highly variable among patients (i.e., 973 ± 501 ng/ml, CV = 52%), calling for implementing TDM in patients with mRCC to monitor exposure levels and evaluate concentration-response relationship.


Assuntos
Anilidas/sangue , Antineoplásicos/sangue , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Espectrometria de Massas/métodos , Piridinas/sangue , Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Modelos Lineares , Piridinas/uso terapêutico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
9.
Biomed Chromatogr ; 34(4): e4802, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31998982

RESUMO

Filgotinib is a selective JAK1 (Janus kinase) inhibitor, filed in Japan for the treatment of rheumatoid arthritis. In this paper, we report a validated liquid chromatography coupled with tandem mass spectrometry for the quantification of filgotinib in rat plasma using tofacitinib as an internal standard (IS) as per the Food and Drug Administration regulatory guidelines. Filgotinib and the IS were extracted from rat plasma using ethyl acetate as an extraction solvent and chromatographed using an isocratic mobile phase (0.2% formic acid:acetonitrile; 20:80, v/v) at a flow rate of 0.9 mL/min on a Gemini C18 column. Filgotinib and the IS were eluted at ~1.31 and 0.89 min, respectively. The MS/MS ion transitions monitored were m/z 426.3 → 291.3 and m/z 313.2 → 149.2 for filgotinib and the IS, respectively. The calibration range was 0.78-1924 ng/mL. No matrix effect and carryover were observed. Intra- and inter-day accuracies and precisions were within the acceptance range. Filgotinib was stable for three freeze-thaw cycles: on bench-top up to 6 h, in an autosampler up to 21 h, and at -80°C for 1 month. This novel method has been applied to a pharmacokinetic study in rats.


Assuntos
Cromatografia Líquida/métodos , Piridinas/sangue , Piridinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Triazóis/sangue , Triazóis/farmacocinética , Animais , Estabilidade de Medicamentos , Modelos Lineares , Masculino , Piridinas/química , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Triazóis/química
10.
Eur J Med Chem ; 188: 112012, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31911293

RESUMO

Starting from a bipyridine-sulfonamide scaffold, medicinal chemistry optimization leads to the discovery of a novel Plasmodium falciparum PI4K kinase (PfPI4K) inhibitor compound 15g (CHMFL-PI4K-127, IC50: 0.9 nM), which exhibits potent activity against 3D7 Plasmodium falciparum (P. falciparum) (EC50: 25.1 nM). CHMFL-PI4K-127 displays high selectivity against PfPI4K over human lipid and protein kinase. In addition, it exhibits EC50 values of 23-47 nM against a panel of the drug-resistant strains of P. falciparum. In vivo, the inhibitor demonstrates the favorable pharmacokinetic properties in both rats and mice. Furthermore, oral administration of CHMFL-PI4K-127 exhibits the antimalaria efficacy in both blood stage (80 mg/kg) and liver stage (1 mg/kg) of Plasmodium in infected rodent model. The results suggest that CHMFL-PI4K-127 might be a new potential drug candidate for malaria.


Assuntos
1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , Antimaláricos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Fígado/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Piridinas/farmacologia , 1-Fosfatidilinositol 4-Quinase/metabolismo , Animais , Antimaláricos/sangue , Antimaláricos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/química , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/metabolismo , Piridinas/sangue , Piridinas/química , Relação Estrutura-Atividade
11.
Int J Clin Oncol ; 25(4): 531-540, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31807967

RESUMO

BACKGROUND: Regorafenib is a multiple tyrosine kinase inhibitor, and the use of this drug is approved for the treatment of cancers that are resistant to chemotherapy, which include advanced colorectal cancer, gastrointestinal stromal tumor, and hepatocellular carcinoma. However, the drug causes adverse events, including skin toxicities that require dose modification in approximately 75% of cases. At present, the blood concentration of regorafenib is not assessed in clinical settings; thus, we recently developed a method that can assess the blood concentration of the drug using high-performance liquid chromatography. METHODS: We measured the trough blood concentrations (Ctrough) of regorafenib and its metabolites (M2 and M5) in 14 and 4 patients with advanced colorectal cancer and gastrointestinal stromal tumor, respectively, using high-performance liquid chromatography. Then, the correlation between the Ctrough and therapeutic outcomes of regorafenib was analyzed. RESULTS: In patients who were receiving regorafenib 40-160 mg/day, the Ctrough values of regorafenib, M2, and M5 were 318-9467, 34-3594, and 38-3796 ng/mL, respectively. The difference in the values was significant. Although the specific factors influencing this difference were not elucidated, the Ctrough of regorafenib was extremely lower in some patients, even though the drug was administered at a standard dose, which may explain the lower response rate. Moreover, the Ctrough value of M5 was significantly correlated to the incidence of skin toxicities, which is the most frequent cause of dose modification. CONCLUSIONS: The use of regorafenib may not be suitable in patients with a low Ctrough value. To prevent skin toxicities, the Ctrough value of M5 should be monitored.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Compostos de Fenilureia/efeitos adversos , Piridinas/efeitos adversos , Dermatopatias/induzido quimicamente , Pele/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/sangue , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/patologia , Citocromo P-450 CYP3A/genética , Monitoramento de Medicamentos/métodos , Feminino , Tumores do Estroma Gastrointestinal/patologia , Glucuronosiltransferase/genética , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Compostos de Fenilureia/sangue , Compostos de Fenilureia/metabolismo , Compostos de Fenilureia/uso terapêutico , Polimorfismo de Nucleotídeo Único , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/sangue , Piridinas/metabolismo , Piridinas/uso terapêutico , Resultado do Tratamento
12.
Heart Vessels ; 35(3): 409-416, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31522245

RESUMO

Direct oral anticoagulants, including edoxaban, primarily do not need routine monitoring of the anticoagulant effect. However, extremely high/low plasma concentrations of edoxaban (PC-Ed) should be properly evaluated, especially when patients under anticoagulation therapy are at an emergency state. For this purpose, PC-Ed determined by an anti-Xa assay (indirect PC-Ed) is more convenient and, therefore, more useful compared with PC-Ed determined by an LC-MS/MS (direct PC-Ed) in daily clinical practice. Consecutive 97 patients with non-valvular atrial fibrillation (NVAF) under edoxaban therapy were evaluated, in whom edoxaban 60/30 mg doses were prescribed for 48/49 patients, 71 (73.2%) were men, and the average age was 69 years. CHADS2 score 0, 1, and ≥ 2 were 26.8%, 44.3%, and 28.9%, while CHA2DS2-VASc score 0, 1, and ≥ 2 were 14.4%, 16.5%, and 69.1%, respectively. Median values of direct and indirect PC-Ed by LC-MS/MS and anti-Xa assay were 187.1 and 176.1 ng/mL at peak (2-4 h post-dose) and 14.4 and 17.5 ng/mL at trough (pre-dose), respectively. The PC-Ed at peak and trough by two methods were significantly correlated, and the correlation coefficients were r = 0.973 and 0.963 (both, p < 0.0001), respectively. By a Bland-Altman plot, mean differences between the direct and indirect PC-Ed [lower to upper percent limit of agreement] were - 4.87 [- 46.71 to 36.98] and 4.66 [- 1.37 to 10.69] ng/mL at peak and trough, respectively. Moreover, mean % error for difference between the direct and indirect PC-Ed [lower to upper percent limit of agreement] was - 1.22 [- 20.59 to 18.14] and 31.75 [- 14.03 to 77.53] % at peak and trough, respectively, where the % error extremely increased around the lower limit of detection (LLOD) in the anti-Xa assay. Strong similarity was observed between the direct and indirect PC-Ed, especially at peak. The indirect PC-Ed was higher than the direct PC-Ed, especially around the LLOD, suggesting the need for caution when we use the anti-Xa assay for measurement of trough PC-Ed (UMIN 000032492).


Assuntos
Fibrilação Atrial/tratamento farmacológico , Testes de Coagulação Sanguínea , Coagulação Sanguínea/efeitos dos fármacos , Cromatografia Líquida , Monitoramento de Medicamentos , Inibidores do Fator Xa/sangue , Piridinas/sangue , Espectrometria de Massas em Tandem , Tiazóis/sangue , Idoso , Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Sistema de Registros , Reprodutibilidade dos Testes , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Resultado do Tratamento
13.
Ther Drug Monit ; 41(5): 657-664, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31568234

RESUMO

BACKGROUND: Under certain circumstances, clinicians treating patients with isavuconazole for invasive aspergillosis or mucormycosis may use therapeutic drug monitoring. However, the accuracy and reproducibility of the various assays used by different laboratories for the quantification of isavuconazole plasma concentrations have yet to be determined. METHODS: Human plasma samples spiked with known concentrations of isavuconazole were provided to 27 European laboratories that took part in a "round-robin" test (an interlaboratory test performed independently at least 2 times; 2 rounds performed in the current study). Assay methods included liquid chromatography-tandem mass spectrometry (LC-MS/MS), LC with ultraviolet detection (LC-UV), LC with fluorescence detection (LC-FL), and bioassay. The accuracy and reproducibility compared with the known concentrations for each sample in each round were compared overall, between assays, and between laboratories. RESULTS: Twenty-seven laboratories participated in the study (LC-MS/MS, n = 15; LC-UV; n = 9; LC-FL, n = 1; bioassay, n = 2). In round 1, for nominal concentrations of 1000, 1700, 2500, and 4000 ng/mL, the mean (SD) determined concentrations were 1007 (183), 1710 (323), 2528 (540), and 3898 (842) ng/mL, respectively. In round 2, for nominal concentrations of 1200, 1800, 2400, and 4000 ng/mL, the mean (SD) determined concentrations were 1411 (303), 2111 (409), 2789 (511), and 4723 (798) ng/mL, respectively. Over both rounds, determined concentrations were consistently within 15% of the nominal concentrations for 10 laboratories (LC-MS/MS, n = 4; LC-UV, n = 5; bioassay, n = 1) and consistently exceeded the upper 15% margin for 7 laboratories (LC-MS/MS and LC-UV, n = 3 each; LC-FL, n = 1). CONCLUSIONS: Alignment of methodologies among laboratories may be warranted to improve the accuracy and reproducibility of therapeutic drug measurements.


Assuntos
Bioensaio/métodos , Nitrilos/sangue , Plasma/química , Piridinas/sangue , Triazóis/sangue , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Europa (Continente) , Humanos , Laboratórios , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
14.
Drug Des Devel Ther ; 13: 3127-3136, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564829

RESUMO

Purpose: S-1 is an oral fluoropyrimidine anticancer drug consisting of the 5-fluorouracil prodrug tegafur combined with gimeracil and oteracil. The purpose of this study was to evaluate the pharmacokinetic (PK), bioequivalence, and safety of a newly developed generic formulation of S-1 compared with the branded reference formulation, in Korean gastric cancer patients. Methods: This was a single-center, randomized, open-label, single-dose, two-treatment, two-way crossover study. Eligible subjects were randomly assigned in a 1:1 ratio to receive the test formulation or reference formulation, followed by a one-week washout period and administration of the alternate formulation. Serial blood samples were collected at 0 hrs (predose), 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hrs after dosing in each period. The plasma concentrations of tegafur, 5-FU, gimeracil, and oteracil were analyzed using a validated liquid chromatography-tandem mass spectrometry method. The PK parameters were calculated using a non-compartmental method. Results: In total, 29 subjects completed the study. All of the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) fell within the predetermined acceptance range. No serious adverse events were reported during the study. Conclusion: The new S-1 formulation met the Korean regulatory requirement for bioequivalence. Both S-1 formulations were well tolerated in all subjects.Clinical trial registry: https://cris.nih.go.kr CRIS KCT0003855.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Antineoplásicos/farmacocinética , Fluoruracila/farmacocinética , Ácido Oxônico/farmacocinética , Piridinas/farmacocinética , Neoplasias Gástricas/metabolismo , Tegafur/farmacocinética , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Cromatografia Líquida , Estudos Cross-Over , Composição de Medicamentos , Fluoruracila/administração & dosagem , Fluoruracila/sangue , Humanos , Ácido Oxônico/administração & dosagem , Ácido Oxônico/sangue , Piridinas/administração & dosagem , Piridinas/sangue , República da Coreia , Neoplasias Gástricas/química , Espectrometria de Massas em Tandem , Tegafur/administração & dosagem , Tegafur/sangue , Equivalência Terapêutica
15.
J Pharm Biomed Anal ; 176: 112735, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31394305

RESUMO

Alflutinib, or known as AST2818, is an irreversible tyrosine kinase inhibitor that selectively inhibits EGFR mutations, especially T790M. At present, alflutinib has undergone phase II/III clinical trials for non-small cell lung cancer (NSCLC) treatment in China. The present study aimed to analye the pharmacokinetics of alflutinib and its active metabolite AST5902 in a plasma sample of NSCLC patient. A sensitive and highly selective method was optimized and validated for the detection of alflutinib and AST5902 using a liquid chromatography-tandem mass spectrometry. After precipitating proteins with acetonitrile, alflutinib, AST5902 and AST2818-d3 (internal standard) were analyzed with a Waters BEH C18 column. The mobile phase was optimized with acetonitrile: ammonium acetate (2 mmol/L) containing 0.2% formic acid using gradient elution. Separation was achieved within a total chromatographic running time of 2.1 min. Quantification was carried out using positive ion multiple reaction monitoring mode at ion transitions m/z 569.3→441.2, 555.1→498.2 and 572.3→441.2 for alflutinib, AST5902 and AST2818-d3, respectively. An excellent linearity was observed for alflutinib and AST5902 within concentration ranges of 0.20-100 and 0.050-25.0 ng·mL-1, respectively. Notably, the lower limit of quantification for alflutinib and AST5902 were 0.20 and 0.050 ng/mL, respectively. The intra- and inter-day accuracy of alflutinib were 0.7-2.9%, while its intra- and inter-assay precision were ≤9.1% and ≤10.5%, respectively. The accuracy of AST5902 was within -0.2-3.9%, while the intra- and inter-assay precision were ≤8.0% and ≤8.6%, respectively. The recoveries of the analysts remained constant and could be reproduced at different concentrations. Furthermore, this analytical method could be applied to determine the pharmacokinetic analysis of alflutinib and AST5902 in human plasma.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Indóis/análise , Neoplasias Pulmonares/tratamento farmacológico , Mesilatos/química , Inibidores de Proteínas Quinases/sangue , Piridinas/sangue , Pirimidinas/sangue , Administração Oral , Carcinoma Pulmonar de Células não Pequenas/sangue , Cromatografia Líquida de Alta Pressão/métodos , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Receptores ErbB/antagonistas & inibidores , Estudos de Viabilidade , Humanos , Indóis/administração & dosagem , Indóis/sangue , Indóis/farmacocinética , Neoplasias Pulmonares/sangue , Mesilatos/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Espectrometria de Massas em Tandem/métodos
16.
Eur J Pharm Sci ; 139: 105041, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31404621

RESUMO

NEPA is the fixed combination antiemetic composed of the neurokinin-1 receptor antagonist netupitant and the 5-hydroxytryptamine-3 receptor antagonist palonosetron. The intravenous (i.v.) formulation of NEPA (fosnetupitant 235 mg/palonosetron 0.25 mg) was developed to enhance the convenience of NEPA administration. In a phase 3 study, i.v. NEPA showed acceptable safety with low risk for injection-site reactions. This study evaluated the pharmacokinetics and safety of i.v. NEPA in cancer patients. This was a single-center, single-dose phase 1 study in patients receiving highly emetogenic chemotherapy. Patients received a 30-min infusion of i.v. NEPA plus oral dexamethasone (12 mg) prior to chemotherapy, and oral dexamethasone (8 mg/daily) on days 2-4. Twenty-four patients received the complete i.v. NEPA infusion volume. Fosnetupitant maximum plasma concentration (Cmax) was reached at the end of infusion and decreased to <1% of Cmax 30 min later. Netupitant was rapidly released from its prodrug and Cmax of 590 ng/ml was reached at the end of fosnetupitant infusion, with a mean exposure (AUC∞) of 15,588 h∙ng/ml. Palonosetron Cmax was reached at the end of infusion, with a mean AUC∞ of 36.07 h∙ng/ml. The most common adverse events were constipation (29%), nausea (17%), and vasospasm (8%). No i.v. NEPA-related injection site reactions occurred. Fosnetupitant conversion to netupitant occurred rapidly in cancer patients. Netupitant and palonosetron pharmacokinetic profiles in i.v. NEPA were similar to those reported for oral NEPA. i.v. NEPA was well tolerated with a similar safety profile to oral NEPA. i.v. NEPA provides additional administration convenience. Clinical trial registration number: EudraCT 2015-004750-18.


Assuntos
Antieméticos/farmacocinética , Isoquinolinas/farmacocinética , Neoplasias/metabolismo , Piridinas/farmacocinética , Quinuclidinas/farmacocinética , Administração Intravenosa , Adulto , Idoso , Antieméticos/administração & dosagem , Antieméticos/efeitos adversos , Antieméticos/sangue , Combinação de Medicamentos , Feminino , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Isoquinolinas/sangue , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/prevenção & controle , Neoplasias/tratamento farmacológico , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/sangue , Quinuclidinas/administração & dosagem , Quinuclidinas/efeitos adversos , Quinuclidinas/sangue , Vômito/induzido quimicamente , Vômito/prevenção & controle
17.
Artigo em Inglês | MEDLINE | ID: mdl-31427296

RESUMO

Isavuconazole plasma concentrations were measured before and after sustained low-efficiency dialysis (SLED) treatment in 22 critically ill adult patients with probable invasive aspergillosis and underlying hematological malignancies. Isavuconazole levels were significantly lower after SLED treatment (5.73 versus 3.36 µg/ml; P < 0.001). However, even after SLED treatment, isavuconazole concentrations exceeded the in vivo MICs for several relevant Aspergillus species.


Assuntos
Antifúngicos/sangue , Antifúngicos/uso terapêutico , Estado Terminal/terapia , Nitrilos/sangue , Nitrilos/uso terapêutico , Piridinas/sangue , Piridinas/uso terapêutico , Triazóis/sangue , Triazóis/uso terapêutico , Adulto , Aspergilose/sangue , Aspergilose/tratamento farmacológico , Aspergillus/efeitos dos fármacos , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade
18.
Biomed Chromatogr ; 33(11): e4658, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31325170

RESUMO

Isocitrate dehydrogenase (IDH) inhibitors comprise a novel class of anticancer drugs, which are approved to treat acute myeloid leukemia patients having mutations on IDH1/2. We report the development and validation of a high-performance liquid chromatography (HPLC) method for the simultaneous quantitation of IDH inhibitors, namely enasidenib (EDB), ivosidenib (IDB) and vorasidenib (VDB), in mouse plasma as per the US Food and Drug Administration regulatory guidelines. The method involves extraction of EDB, IDB and VDB along with internal standard (IS; phenacetin) from mouse plasma (100 µl) using a simple protein precipitation process. The chromatographic analysis was performed on an HPLC system using a gradient mobile phase (comprising 10 mm ammonium acetate and acetonitrile in a flow-gradient) and an X-Terra Phenyl column. The UV detection wave length was set at λmax 265 nm. EDB, IDB, VDB and the IS eluted at 7.36, 8.60, 9.50 and 5.12 min, respectively, with a total run time of 10 min. The calibration curve was linear over a concentration range of 0.20-12.5 µg/ml for EDB and 0.50-12.5 µg/ml for IDB and VDB (r2  = ≥0.998 for all of the analytes). Validation results met the acceptance criteria. The validated HPLC method was successfully applied to a pharmacokinetic study in mice.


Assuntos
Aminopiridinas/sangue , Antineoplásicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Piridinas/sangue , Triazinas/sangue , Aminopiridinas/química , Aminopiridinas/farmacocinética , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Estabilidade de Medicamentos , Glicina/sangue , Glicina/química , Glicina/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Piridinas/química , Piridinas/farmacocinética , Reprodutibilidade dos Testes , Triazinas/química , Triazinas/farmacocinética
19.
Biomed Chromatogr ; 33(10): e4611, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31145820

RESUMO

In this study, a simple and reliable liquid chromatography coupled with Q-Exactive-Orbitrap-MS was developed and validated for detecting and quantifying cligosiban and its metabolites in dog plasma after oral administration. The plasma samples were pretreated with acetonitrile and separated on a Diamonsil C18 column (4.6 × 100 mm, i.d. 3 µm) with 0.1% formic acid in water and acetonitrile as mobile phase. The method was validated according to the guidance of the US Food and Drug Administration. The assay was linear over the tested concentration ranges with coefficients of correlation >0.995. The extraction recovery was >83.23% with RSD <15%. Precision was <9.31% and accuracy ranged from -4.40 to 10.20%. The method was free of matrix effects. Under the conditions used, four metabolites were detected and their identities were identified by accurate masses and fragment ions. M1 and M3 were further confirmed by reference standards. The biotransformation pathways included demethylation and glucuronidation. The validated method was further applied to quantify cligosiban, M1 and M3 in dog plasma. After oral administration, cligosiban was detectable in dog plasma and reached the maximum concentration at ~1.67 ± 0.58 h post-dose. It was rapidly eliminated with a half-life of 3.48 ± 0.80 h. M1 showed high plasma exposure with its area under the curve being 23.31% of that of cligosiban.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Piridinas/sangue , Piridinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Triazóis/sangue , Triazóis/farmacocinética , Administração Oral , Animais , Cães , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Masculino , Piridinas/administração & dosagem , Piridinas/química , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos , Triazóis/administração & dosagem , Triazóis/química
20.
Ther Drug Monit ; 41(4): 489-496, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31083044

RESUMO

BACKGROUND: Apatinib is a new oral micromolecular tyrosine kinase inhibitor, which is mainly used as a third-line treatment for chemotherapy-refractory advanced metastatic gastric cancer patients. However, apatinib has shown dose titration and severe adverse reactions in clinical practice. Quantification of plasma concentrations of apatinib may be an effective method to balance the clinical efficacy and adverse reactions. The purpose of this study was to develop and validate a 2-dimensional liquid chromatography method for the measurement of apatinib in plasma. METHODS: The analysis of apatinib was performed using a 2-dimensional high-performance liquid chromatography system. We precipitated the proteins with acetonitrile. The mobile phases consisted of a first-dimensional mobile phase (acetonitrile:methanol:25 mmol·L ammonium phosphate = 25:25:50, V/V/V, pH adjusted to 7.2 using phosphoric acid) and a second-dimensional mobile phase (acetonitrile:10 mmol·L ammonium phosphate = 28:72, vol/vol, pH adjusted to 3.7 using phosphoric acid). The ultraviolet detection wavelength was set at 340 nm. The temperature of the detector cell was 40°C, and the injection volume was 500 µL. RESULTS: The range of calibration curve was 15.27-1491.48 ng/mL. The accuracy and imprecision were within ±2.23% and less than 10.22%, respectively (intraday and interday). The range of recovery was 97.45%-108.92%. The intraday and interday relative SDs (reproducibility) of high-performance liquid chromatography retention times were less than 0.18% and 0.46%, respectively. In the clinical assessment, the dose range of apatinib mesylate for patients with gastric cancer was 250-500 mg every day (2-60 days), resulting in trough plasma concentrations between 272.7 and 727.8 ng/mL. CONCLUSIONS: A simple, convenient, accurate, and robust 2-dimensional liquid chromatography method was developed and verified, which successfully determined the plasma concentrations of apatinib in patients with gastric cancer.


Assuntos
Plasma/química , Piridinas/sangue , Calibragem , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/métodos , Humanos , Limite de Detecção , Reprodutibilidade dos Testes
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