RESUMO
Cystic fibrosis is one of the most common genetic diseases among caucasian population. This disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding for the CFTR protein. Lumacaftor, elexacaftor, tezacaftor, and ivacaftor were currently used as the treatment to Cystic fibrosis. In this study, we describe a new method for the simultaneous quantification of four molecules: lumacaftor, elexacaftor, tezacaftor, and ivacaftor, alongside two metabolites of ivacaftor, specifically hexyl-methyl ivacaftor and ivacaftor carboxylate by liquid chromatography-tandem mass spectrometry. This method holds significant utility for therapeutic drug monitoring and the optimization of treatments related to CFTR modulators. Molecules were extracted from 100⯵L of plasma by a simple method of protein precipitation using acetonitrile. Following extraction, chromatographic separation was carried out by reverse chromatography on a C18 analytical column, using a gradient elution of water (0.05â¯% formic acid, V/V) and acetonitrile (0.05â¯% formic acid, V/V). The run time was 7â¯minutes at a flow rate of 0.5â¯mL/min. After separation, molecules were detected by electrospray ionization on a Xevo TQD triple-quadrupole-mass-spectrometer (Waters®, Milford, USA). The calibration range were: 0.053-20.000â¯mg/L for elexacaftor, tezacaftor and lumacaftor, 0.075-14.000â¯mg/L for ivacaftor, and 0.024-6.500â¯mg/L for hexyl-methyl ivacaftor and ivacaftor carboxylate. The proposed method underwent throughout validation demonstrating satisfactory precision (inter- and intra-day coefficients of variation less than 14.3â¯%) and a good accuracy (inter- and intra-day bias ranging between -13.7â¯% and 14.7â¯%) for all the analytes. The presented method for the simultaneous quantification of CFTR modulators and their metabolites in human plasma has undergone rigorous validation process yielding good results including strong precision and accuracy for all analytes. This method has been effectively used in routine analytical analysis and clinical investigations within our laboratory.
Assuntos
Aminofenóis , Aminopiridinas , Benzodioxóis , Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Indóis , Quinolonas , Humanos , Aminofenóis/sangue , Aminofenóis/farmacocinética , Aminopiridinas/sangue , Aminopiridinas/farmacocinética , Benzodioxóis/sangue , Benzodioxóis/farmacocinética , Fibrose Cística/tratamento farmacológico , Fibrose Cística/sangue , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Monitoramento de Medicamentos/métodos , Indóis/sangue , Indóis/farmacocinética , Espectrometria de Massa com Cromatografia Líquida , Pirazóis/sangue , Pirazóis/farmacocinética , Piridinas , Pirróis/sangue , Pirróis/farmacocinética , Pirrolidinas , Quinolonas/sangue , Quinolonas/farmacocinética , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodosRESUMO
BACKGROUND: Eltrombopag Olamine is a drug used to treat thrombocytopenia, a disorder where blood platelet counts get lower and severe aplastic anemia. It serves as a thrombopoietin receptor agonist, which give rise to platelet production in the bone marrow. OBJECTIVES: The objective of this study is to develop a simple, specific, accurate, precise and economical Ultraviolet spectroscopy method to estimate the amount of Eltrombopag Olamine in bulk and tablet dosage form. METHODS: The developed method was performed using methanol for identification and physicochemical characterization of the drug. The validation parameters like linearity, precision, accuracy, robustness limits of detection and quantitation, and specificity were assessed as per ICH Q2 (R2). RESULTS: The maximum absorbance wavelength (λmax) of the drug was found at 247 nm in methanol. The linearity was found in the concentration range of 2-14 µg/ml with regression equation y = 0.0619x - 0.0123 and r² = 0.999. The standard addition method was used to determine the accuracy of the developed method. The result was found in the % recovery range of 98-99%. The precision was done on λmax with respect to the parameters such as repeatability, intraday, and interday. The method was found to be precise as the % RSD value was found to be <2%. The detection limit value (LOD) and quantitation limit value (LOQ) were 0.0524 µg/ml and 0.1588 µg/ml, respectively. CONCLUSION: The developed method is simple, economical, accurate and selective. The developed method was adaptable for the estimation of Eltrombopag Olamine analysis in pharmaceutical dosage form and routine quality control laboratory.
Assuntos
Benzoatos , Hidrazinas , Pirazóis , Espectrofotometria Ultravioleta , Comprimidos , Pirazóis/análise , Pirazóis/sangue , Pirazóis/química , Benzoatos/análise , Benzoatos/química , Benzoatos/sangue , Hidrazinas/análise , Hidrazinas/química , Espectrofotometria Ultravioleta/métodos , Limite de Detecção , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Catheter ablation in patients with atrial fibrillation is associated with a transient increase in thromboembolic risk and adequate anticoagulation is highly important. When patients are anticoagulated with apixaban, monitoring of plasma concentrations of the drug is not routinely performed. This study aimed to assess the influence of clinical patient characteristics, concomitant drug treatment and self-reported adherence on apixaban concentrations, and to describe the intra- and inter-individual variability in apixaban concentrations in this group of patients. Method Apixaban concentrations from 141 patients were measured in plasma one week before ablation and two, six and ten weeks after ablation, employing ultra-high performance liquid chromatography coupled with tandem mass spectrometry. In samples not obtained at trough, apixaban concentrations were adjusted to trough levels. Self-reported adherence was registered by means of the 8-item Morisky Medication Adherence Scale before and after ablation. RESULTS: There were statistically significant, positive correlations between apixaban concentrations and increased age, female sex, lower glomerular filtration rate, higher CHA2DS2-VASc score, use of cytochrome P450 3A4 and/or p-glycoprotein inhibitors, and use of amiodarone. Self-reported adherence was generally high. The mean intra-individual and inter-individual coefficients of variation were 29% and 49%, respectively. CONCLUSION: In patients undergoing catheter ablation for atrial fibrillation, age, sex, renal function, interacting drugs and cerebrovascular risk profile were all associated with altered plasma apixaban concentration. In this group of patients with a generally high self-reported adherence, intra-individual variability was modest, but the inter-individual variability was substantial, and similar to those previously reported in other patient apixaban-treated populations. If a therapeutic concentration range is established, there might be a need for a more flexible approach to apixaban dosing, guided by therapeutic drug monitoring.
Assuntos
Fibrilação Atrial , Ablação por Cateter , Pirazóis , Piridonas , Humanos , Piridonas/sangue , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/cirurgia , Fibrilação Atrial/sangue , Pirazóis/sangue , Pirazóis/uso terapêutico , Pirazóis/farmacocinética , Pirazóis/administração & dosagem , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Inibidores do Fator Xa/sangue , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/uso terapêutico , Adesão à MedicaçãoRESUMO
Ibrutinib, an antineoplastic agent tackling chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's Macroglobulinemia, falls under the category of BCS class II drugs, characterized by a puzzling combination of low solubility and high permeability. Its oral bioavailability remains a perplexing challenge, merely reaching 2.9 % due to formidable first-pass metabolism hurdles. In a bid to surmount this obstacle, researchers embarked on a journey to develop ibrutinib-loaded NLCs (Nanostructured Lipid Carriers) using a methodology steeped in complexity: a Design of Experiments (DoE)-based hot melted ultrasonication approach. Despite a plethora of methods for analyzing ibrutinib in various matrices, the absence of a spectrofluorimetric method for assessing it in rat plasma added to the enigma. Thus emerged a spectrofluorimetric method, embodying principles of white analytical chemistry and analytical quality by design, employing a Placket-Burman design for initial method exploration and a central composite design for subsequent refinement. This method underwent rigorous validation in accordance with ICH guidelines, paving the way for its application in scrutinizing the in-vivo pharmacokinetics of ibrutinib-loaded NLCs, juxtaposed against commercially available formulations. Surprisingly, the optimized NLCs exhibited a striking 1.82-fold boost in oral bioavailability, shedding light on their potential efficacy. The environmental impact of this method was scrutinized using analytical greenness tools, affirming its eco-friendly attributes. In essence, the culmination of these efforts has not only propelled advancements in drug bioavailability but also heralded the dawn of a streamlined and environmentally conscious analytical paradigm.
Assuntos
Adenina , Lipídeos , Piperidinas , Pirimidinas , Espectrometria de Fluorescência , Animais , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/química , Adenina/sangue , Piperidinas/farmacocinética , Piperidinas/química , Piperidinas/sangue , Lipídeos/química , Masculino , Espectrometria de Fluorescência/métodos , Ratos , Pirimidinas/farmacocinética , Pirimidinas/química , Pirimidinas/sangue , Portadores de Fármacos/química , Nanoestruturas/química , Pirazóis/farmacocinética , Pirazóis/química , Pirazóis/sangue , Pirazóis/administração & dosagem , Reprodutibilidade dos Testes , Ratos WistarRESUMO
OBJECTIVES: Apixaban, a direct oral anticoagulant, is increasingly used worldwide for the treatment and prevention of venous thromboembolism and ischemic stroke in patients with nonvalvular atrial fibrillation (AF). Obviously, one of the ways to enhance effectiveness and safety of drug therapy is a personalized approach to therapy, which involves pharmacogenetic and pharmacokinetic tests. The study aims to investigate the effect of CYP3A4*22, CYP3A5*3 and ABCB1 polymorphisms on the pharmacokinetics of apixaban and the risk of bleeding. METHODS: A total of 84 patients were enrolled in this prospective observational study. All patients received apixaban 5 or 2.5â¯mg twice daily. Real-time polymerase chain reaction was used to evaluate single-nucleotide polymorphisms of the ABCB1 gene (rs1045642 and rs4148738), CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G. A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index. RESULTS: The C/D ratio was higher in patients aged >80 years (F(1)=11.209, p=0.00124) and was affected by serum creatinine (>133⯵mol/L, F(1)=6.7, p=0.01124). ABCB1 (rs1045642 and rs4148738), CYP3A5 (rs776746) and CYP3A4 (rs35599367) polymorphisms did not show a correlation with C/D ratio of apixaban. Multivariate logistic regression analyses showed that none of the clinical or genetic factors predicted the fact of bleeding. CONCLUSIONS: We report no significant association between ABCB1 gene polymorphisms (rs1045642 and rs4148738), CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G and bleeding events on apixaban treatment. Complementing the existing criteria with pharmacogenetic and pharmacokinetics information for the patients with AF will enable further individualization of apixaban.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Fibrilação Atrial , Citocromo P-450 CYP3A , Hemorragia , Polimorfismo de Nucleotídeo Único , Pirazóis , Piridonas , Humanos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/genética , Piridonas/farmacocinética , Piridonas/efeitos adversos , Piridonas/administração & dosagem , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Masculino , Feminino , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Pirazóis/farmacocinética , Pirazóis/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/sangue , Pirazóis/uso terapêutico , Idoso , Hemorragia/induzido quimicamente , Hemorragia/genética , Estudos Prospectivos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/administração & dosagemRESUMO
PURPOSE: Routine therapeutic drug monitoring of apixaban is currently not recommended but may however be warranted in some situations and for some patient groups to provide better and safer treatment. Due to limited data on apixaban concentrations in different subpopulations, it is still unclear which group of patients could possibly gain from monitoring. The purpose of this study was to examine apixaban exposure in patients with obesity compared with normal-weight patients. METHODS: Forty patients with obesity (mean BMI 39.4 kg/m2) and 40 controls with normal weight (mean BMI 23.4 kg/m2), treated with apixaban 5 mg twice daily were included. The patients were matched for age, sex, and renal function. Trough and peak apixaban concentrations were measured with LCâMS/MS methodology. RESULTS: The median trough concentrations in patients with obesity (58.7, range 10.7-200.7 ng/ml) were slightly higher than those in patients with normal weight (52.0, range 31.0-150.9 ng/ml) (p < 0.05). Notably, the variability in trough concentration was considerably higher in patients with obesity. Peak concentrations were similar in both groups, with a median of 124.5 ng/ml (range 82.0-277.5) and 113.5 ng/ml (range 75.5-334.6) in patients with obesity and normal weight, respectively. CONCLUSION: Apixaban exposure did not vary substantially between obese and normal weight matched controls, implying that general dose adjustments are not required. However, vast interindividual variability was observed in patients with obesity, suggesting that measuring the concentrations could be valuable for specific patients. Further research is needed to identify which specific patients may benefit from this approach.
Assuntos
Monitoramento de Medicamentos , Inibidores do Fator Xa , Obesidade , Pirazóis , Piridonas , Humanos , Piridonas/sangue , Piridonas/farmacocinética , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Pirazóis/sangue , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Feminino , Obesidade/sangue , Masculino , Pessoa de Meia-Idade , Inibidores do Fator Xa/sangue , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/administração & dosagem , Adulto , Idoso , Monitoramento de Medicamentos/métodos , Espectrometria de Massas em Tandem , Estudos de Casos e ControlesRESUMO
Brepocitinib is an oral once-daily Janus kinase 1 and Tyrosine kinase 2 selective inhibitor currently in development for the treatment of several autoimmune disorders. Mass balance and metabolic profiles were determined using accelerator mass spectrometry in six healthy male participants following a single oral 60 mg dose of 14C-brepocitinib (â¼300 nCi). The average mass balance recovery was 96.7% ± 6.3%, with the majority of dose (88.0% ± 8.0%) recovered in urine and 8.7% ± 2.1% of the dose recovered in feces. Absorption of brepocitinib was rapid, with maximal plasma concentrations of total radioactivity and brepocitinib achieved within 0.5 hours after dosing. Circulating radioactivity consisted primarily of brepocitinib (47.8%) and metabolite M1 (37.1%) derived from hydroxylation at the C5' position of the pyrazole ring. Fractional contributions to metabolism via cytochrome P450 enzymes were determined to be 0.77 for CYP3A4/5 and 0.14 for CYP1A2 based on phenotyping studies in human liver microsomes. However, additional clinical studies are required to understand the potential contribution of CYP1A1. Approximately 83% of the dose was eliminated as N-methylpyrazolyl oxidative metabolites, with 52.1% of the dose excreted as M1 alone. Notably, M1 was not observed as a circulating metabolite in earlier metabolic profiling of human plasma from a multiple ascending dose study with unlabeled brepocitinib. Mechanistic studies revealed that M1 was highly unstable in human plasma and phosphate buffer, undergoing chemical oxidation leading to loss of the 5-hydroxy-1-methylpyrazole moiety and formation of aminopyrimidine cleavage product M2. Time-dependent inhibition and trapping studies with M1 yielded insights into the mechanism of this unusual and unexpected instability. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of brepocitinib, a JAK1/TYK2 inhibitor for atopic dermatitis, in humans as well as characterization of clearance pathways and pharmacokinetics of brepocitinib and its metabolites.
Assuntos
Inibidores de Proteínas Quinases , Humanos , Masculino , Adulto , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/metabolismo , Adulto Jovem , Pirazóis/farmacocinética , Pirazóis/metabolismo , Pirazóis/sangue , Pirazóis/administração & dosagem , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Administração Oral , Citocromo P-450 CYP3A/metabolismo , Voluntários Saudáveis , Microssomos Hepáticos/metabolismo , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Fezes/química , Hidroxilação , Citocromo P-450 CYP1A2/metabolismo , Pessoa de Meia-IdadeRESUMO
Herein, we developed a rapid, one-step, and cost-effective methodology based on the fabrication of water-soluble self-nitrogen, sulfur, and phosphorus co-doped black seed carbon quantum dots (BSQDs) via microwaveirradiation in six minutes. Our synthesis approach is superior to those in the literature as they involved long-time heating (12 h) with sulfuric acid and sodium hydroxide and/or high temperatures (200 °C). A full factorial design was applied to obtain the most efficient synthesis conditions.BSQDs displayed excitation-independent emissions, demonstrating the purity of the synthesized BSQDs, with a maximum fluorescence at 425 nm after excitation at 310 nm. Eltrombopag olamine is an anti-thrombocytopenia drug that is also reported to cause toxicity in river water based on its Persistence, Bioaccumulation, and Toxicity (PBT). The synthesized BSQDs were employed as the first fluorometric sensor for environmental and bioanalysis of eltrombopag. The fluorescence of BSQDs decreased with increasing concentrations of eltrombopag, with excellent selectivity and sensitivity down to 30 ppb. BSQDs were successfully applied as sensing probes for the detection of eltrombopag in medical tablets, spiked and real human plasma samples, and river water samples, with an overall recovery of at least 97 %. The good tolerance to high levels of foreign components and co-administered drugs indicates good selectivity and versatility of the proposed methodology. Plasma pharmacokinetic parameters such as t1/2, Cmax, and t max of eltrombopag were evaluated to be 9.91 h, 16.0 µg mL-1, and 5 h, respectively. Moreover, the green character of the BSQDs as a sensor was proved by various analytical greenness scales.
Assuntos
Benzoatos , Carbono , Pirazóis , Pontos Quânticos , Pontos Quânticos/química , Carbono/química , Pirazóis/química , Pirazóis/sangue , Benzoatos/química , Benzoatos/sangue , Humanos , Espectrometria de Fluorescência/métodos , Animais , Nitrogênio/química , Limite de Detecção , Fósforo/química , HidrazinasRESUMO
Unecritinib (TQ-B3101) is a selective tyrosine kinase receptor inhibitor. In the study, in vitro metabolic experiments revealed that the hydrolysis of TQ-B3101 was mainly catalyzed by carboxylesterase 2 (CES2), followed by CES1. Next, a sensitive and reliable LC-MS/MS method was established for the simultaneous determination of TQ-B3101 and its metabolite crizotinib in rat plasma. To prevent in vitro hydrolysis of TQ-B3101, sodium fluoride, the CESs inhibitor at a concentration of 2â¯M, was immediately added after whole blood collection. Plasma samples were extracted by acetonitrile-induced protein precipitation method, and chromatographically separated on a Gemini C18 column (50â¯mm × 2.0â¯mm i.d., 5 µm) using gradient elution with a mobile phase of 0.1% formic acid and 5â¯mmol/L ammonium acetate with 0.1% formic acid. The retention times for TQ-B3101 and crizotinib were 2.61 and 2.38â¯min, respectively. The analytes were detected with tandem mass spectrometer by positive electrospray ionization, using the ion transitions at m/z 492.3 â 302.3 for TQ-B3101, m/z 450.3 â 260.3 for crizotinib, and m/z 494.0 â 394.3 for imatinib (internal standard). Method validation was conducted in the linear range of 1.00-800â¯ng/mL for the two analytes. The precision, accuracy and stabilities all met the acceptance criteria. The pharmacokinetic study indicated that TQ-B3101 was rapidly hydrolyzed to crizotinib with the elimination half-life of 1.11â¯h after a single gavage administration of 27â¯mg/kg to Sprague-Dawley rats, and the plasma exposure of TQ-B3101 was only 2.98% of that of crizotinib.
Assuntos
Crizotinibe , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Animais , Espectrometria de Massas em Tandem/métodos , Crizotinibe/sangue , Crizotinibe/farmacocinética , Ratos , Masculino , Cromatografia Líquida/métodos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/sangue , Reprodutibilidade dos Testes , Hidrólise , Piridinas/sangue , Piridinas/farmacocinética , Pirazóis/sangue , Pirazóis/farmacocinética , Espectrometria de Massa com Cromatografia LíquidaRESUMO
The present study aimed to assess the bioequivalence of a new apixaban generic with reference formulation. Twenty-six healthy volunteers were recruited for an open-label, balanced, randomized, 2-treatment, 2-sequence, 2-period, single oral dose study. Following overnight fasting, each volunteer received 5 mg of apixaban test and reference formulations as single doses, separated by a 1-week washout period. Twenty blood samples were collected at predose and multiple time points between 0.5 and 72 hours after dosing. A validated ultra-performance liquid chromatography-tandem mass spectrometry detection method following a protein precipitation step was implemented to determine apixaban concentrations. Noncompartmental analysis was used to derive the pharmacokinetic parameters, which were then compared between the test and reference products using a multivariate analysis of variance. The pharmacokinetic parameters of the test product were not statistically different from the reference product, and the 90% confidence intervals of apixaban natural log-transformed area under the concentration-time curve from time 0 to infinity, area under the concentration-time curve from time 0 to the last measurable concentration, and maximum concentration were within 80%-125% based on the bioequivalence acceptance range criteria. The test and reference formulations of apixaban are bioequivalent in healthy subjects under fasting conditions.
Assuntos
Estudos Cross-Over , Jejum , Voluntários Saudáveis , Pirazóis , Piridonas , Comprimidos , Equivalência Terapêutica , Humanos , Piridonas/farmacocinética , Piridonas/administração & dosagem , Piridonas/sangue , Pirazóis/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/sangue , Adulto , Masculino , Adulto Jovem , Indonésia , Feminino , Área Sob a Curva , Administração Oral , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/administração & dosagem , Espectrometria de Massas em Tandem/métodos , Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/administração & dosagemRESUMO
INTRODUCTION: Direct oral anticoagulants (DOACs) reflect anticoagulation agents given to treat or prevent thrombosis, having largely replaced vitamin K antagonists (VKAs) such as warfarin. DOACs are given in fixed daily doses and generally do not need monitoring. However, there may be a variety of reasons that justify measurement of plasma DOAC levels in individual patients. METHODS: We report updated findings for DOAC testing in our geographic region, using recent data from the RCPAQAP, an international external quality assessment (EQA) program, currently with some 40-60 participants in each of the different DOAC (rivaroxaban, apixaban, dabigatran) modules, to assess laboratory performance in this area. Data has been assessed for the past 5 years (2019-2023 inclusive), with 20 samples each per DOAC. RESULTS: Data shows a limited repertoire of assays in use, and mostly consistency in reported numerical values when assessing proficiency samples. Available assays mostly comprised reagents from four manufacturing suppliers. There was good consistency across what participants identified as 'DOAC detected', but some variability when participants attempted to grade DOAC levels as low vs moderate vs high. Inter-laboratory/method coefficient of variation (CVs) were generally <15% for each DOAC, when present at >100 ng/mL. CONCLUSION: We hope our findings, reflecting on mostly consistent reporting of DOAC levels and interpretation provides reassurance for clinicians requesting these measurements, and helps support their implementation in regions where there is a paucity of test availability.
Assuntos
Anticoagulantes , Humanos , Administração Oral , Anticoagulantes/administração & dosagem , Testes de Coagulação Sanguínea/normas , Testes de Coagulação Sanguínea/métodos , Hemostasia/efeitos dos fármacos , Rivaroxabana/sangue , Piridonas/administração & dosagem , Australásia , Dabigatrana , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/normas , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Pirazóis/sangueRESUMO
Eltrombopag was approved as a first-line treatment for patients older than 2 years old with severe aplastic anemia (SAA). However, data on eltrombopag in children with different types of aplastic anemia (AA), especially non-severe AA (NSAA), are limited. We performed a prospective, single-arm, and observational study to investigate eltrombopag's efficacy, safety, and pharmacokinetics in children with NSAA, SAA, and very severe AA (VSAA). The efficacy and safety were assessed every 3 months. The population pharmacokinetic (PPK) model was used to depict the pharmacokinetic profile of eltrombopag. Twenty-three AA children with an average age of 7.9 (range of 3.0-14.0) years were enrolled. The response (complete and partial response) rate was 12.5%, 50.0%, and 100.0% after 3, 6, and 12 months in patients with NSAA. For patients with SAA and VSAA, these response rates were 46.7%, 61.5%, and 87.5%. Hepatotoxicity occurred in one patient. Fifty-three blood samples were used to build the PPK model. Body weight was the only covariate for apparent clearance (CL/F) and volume of distribution. The allele-T carrier of adenosine triphosphate-binding cassette transporter G2 was found to increase eltrombopag's clearance. However, when normalized by weight, the clearance between the wild-type and variant showed no statistical difference. In patients with response, children with NSAA exhibited lower area under the curve from time zero to infinity, higher CL/F, and higher weight-adjusted CL/F than those with SAA or VSAA. However, the differences were not statistically significant. The results may support further individualized treatment of eltrombopag in children with AA.
Assuntos
Anemia Aplástica , Benzoatos , Hidrazinas , Pirazóis , Humanos , Benzoatos/farmacocinética , Benzoatos/efeitos adversos , Benzoatos/uso terapêutico , Benzoatos/administração & dosagem , Hidrazinas/farmacocinética , Hidrazinas/efeitos adversos , Hidrazinas/uso terapêutico , Criança , Anemia Aplástica/tratamento farmacológico , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/sangue , Masculino , Pré-Escolar , Feminino , Adolescente , Estudos Prospectivos , Resultado do Tratamento , Modelos Biológicos , Receptores de Trombopoetina/agonistas , Índice de Gravidade de Doença , Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP3A/genéticaRESUMO
BACKGROUND: Routine monitoring of direct oral anticoagulant (DOAC) levels is not recommended but may be useful in certain clinical situations. There is a knowledge gap regarding the clinical use of DOAC levels in Australian hospitals. AIMS: To evaluate the clinical settings, indications and changes to anticoagulant management associated with DOAC levels in a tertiary hospital in Northern Tasmania, Australia. METHODS: Patients with one or more DOAC levels (dabigatran, rivaroxaban or apixaban) requested between January 2017 and December 2022 were identified. Retrospective chart review was performed to evaluate the clinical settings, indications, adequacy of request information and changes to clinical management associated with the measurement of DOAC levels. RESULTS: One hundred and twenty-nine DOAC measurements (54 rivaroxaban, 66 apixaban and nine dabigatran) were performed in 98 patients between January 2017 and December 2022. Annual requests for DOAC levels increased significantly between 2017 and 2019 and remained stable between 2020 and 2021 but declined in 2022. Overall, the most common indication for a DOAC level was renal impairment, followed by bleeding and recurrent thrombosis. Approximately 25% of requests were for acute bleeding with a reversal/haemostatic agent given in 45% of patients, while 10% were prior to urgent surgery. Measurement of DOAC levels was associated with a change in management in 50% of cases. 10% of requests did not specify anticoagulant history. CONCLUSION: Trends in requests for DOAC levels have changed over time. Clinician education regarding the importance of providing specific anticoagulant history is essential. Future prospective studies investigating the clinical utility of DOAC levels in different clinical settings are needed.
Assuntos
Dabigatrana , Pirazóis , Piridonas , Rivaroxabana , Humanos , Estudos Retrospectivos , Tasmânia , Feminino , Masculino , Idoso , Pirazóis/sangue , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Rivaroxabana/sangue , Rivaroxabana/uso terapêutico , Rivaroxabana/administração & dosagem , Piridonas/sangue , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Dabigatrana/sangue , Dabigatrana/uso terapêutico , Dabigatrana/administração & dosagem , Hemorragia/sangue , Monitoramento de Medicamentos/métodos , Administração Oral , Inibidores do Fator Xa/sangue , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/administração & dosagem , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Trombose/sangue , Trombose/prevenção & controleRESUMO
PURPOSE: Lorlatinib is a third-generation tyrosine kinase inhibitor currently approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer. This open-label, phase 1, randomized two-sequence, two-treatment, two-period, crossover study investigated the absolute oral bioavailability of lorlatinib in healthy participants. METHODS: Eligible participants were randomized to receive two treatments in one of two sequences: lorlatinib 100 mg single oral dose followed by lorlatinib 50 mg intravenous (IV) dose, or lorlatinib IV dose followed by lorlatinib oral dose, each with at least a 10-day washout between successive lorlatinib doses. Blood samples for pharmacokinetics were collected for up to 144 hours (h) after dosing. Validated liquid chromatographic-tandem mass spectrometry was used to determine plasma concentrations of lorlatinib and its benzoic acid metabolite PF-06895751. RESULTS: In total, 11 participants were enrolled (mean age 37.6 years, all male). The adjusted geometric mean (90% confidence interval) for the absolute oral bioavailability was 80.78% (75.73-86.16%). Using non-compartmental analysis, the estimated arithmetic mean elimination plasma half-life of lorlatinib was 25.5 and 27.0 h after the oral and IV doses, respectively. No deaths, serious adverse events (AEs), or severe AEs were reported, and most treatment-emergent AEs were mild in severity, with two events of transaminase increase of moderate severity. All treatment-emergent AEs were resolved by the end of the study. CONCLUSION: Both oral and IV lorlatinib were well-tolerated in healthy participants and oral lorlatinib is highly bioavailable after oral administration.
Assuntos
Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Lactamas/administração & dosagem , Lactamas/efeitos adversos , Lactamas/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Administração Oral , Adulto , Aminopiridinas/sangue , Disponibilidade Biológica , Voluntários Saudáveis , Humanos , Injeções Intravenosas , Lactamas/sangue , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/sangueRESUMO
PURPOSE: Erdafitinib (JNJ-42756493, BALVERSA) is a tyrosine kinase inhibitor indicated for the treatment of advanced urothelial carcinoma. In this work, a translational model-based approach to inform the choice of the doses in phase 1 trials is illustrated. METHODS: A pharmacokinetic (PK) model was developed to describe the time course of erdafitinib plasma concentrations in mice and rats. Data from multiple xenograft studies in mice and rats were analyzed using the Simeoni tumor growth inhibition (TGI) model. The model parameters were used to derive a range of erdafitinib exposures that might inform the choice of the doses in oncology phase 1 trials. Conversion of exposures to doses was based on preliminary PK assessments from the first-in human (FIH) study. RESULTS: A one-compartment PK disposition model, with linear absorption and dose-dependent clearance, adequately described the PK data in both mice and rats via an allometric scaling approach. The TGI model was able to describe tumor growth dynamics, providing quantitative measurements of erdafitinib antitumor potency in mice and rats. Based on these estimates, ranges of efficacious unbound concentration were identified for erdafitinib in mice (0.642-5.364 µg/L) and rats (0.782-2.565 µg/L). Based on the FIH data, it was possible to transpose exposures into doses and doses of above 4 mg/day provided erdafitinib exposures associated with significant TGI in animals. The findings were in agreement with the results of the FIH trial, in which the first hints of clinical activities were observed at 6 mg. CONCLUSION: The successful modeling exercise of erdafitinib preclinical data showed how translational PK-PD modeling might be a tool to help to inform the choice of the doses in FIH studies.
Assuntos
Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Quinoxalinas/administração & dosagem , Quinoxalinas/farmacocinética , Pesquisa Translacional Biomédica/métodos , Animais , Ensaios Clínicos Fase I como Assunto , Humanos , Camundongos Nus , Modelos Biológicos , Pirazóis/sangue , Quinoxalinas/sangue , Ratos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
ABSTRACT: Direct-acting oral anticoagulants (DOACs) vary in bioavailability and sites of absorption in the gastrointestinal tract (GIT). Data on DOAC use after major GIT surgery are limited. The aim of this case series was to report the impact of surgical resection or bypass of the GIT on rivaroxaban and apixaban peak plasma concentrations. This was a case series of patients who received rivaroxaban or apixaban after GIT surgery, during the period of July 1, 2019, to December 31, 2020. Peak plasma concentrations of rivaroxaban and apixaban were assessed for the expected concentrations. Of the 27 assessed patients, 18 (66.7%) received rivaroxaban, and 9 (33.3%) received apixaban. After rivaroxaban therapy, 4 of 5 patients (80%) who underwent gastrectomy, and 3 of 3 patients (100%) who underwent duodenum and proximal jejunum exclusion had peak plasma concentrations of rivaroxaban lower than the effective range, whereas 11 of 11 patients (100%) who underwent distal bowel or ileostomy had peak rivaroxaban plasma within the effective range. After apixaban therapy, 5 of 6 patients (83.3%) who underwent total or partial gastrectomy achieved effective peak concentrations. All the patients who underwent proximal and distal bowel resection or bypass had peak concentrations of apixaban within the effective range. In conclusion, surgical resection or bypass of the upper GIT could affect DOAC absorption and subsequently peak plasma concentrations. This effect was more observed among rivaroxaban recipients. An injectable anticoagulant or vitamin K antagonist may be preferred if DOAC concentrations cannot be measured after GIT surgery.
Assuntos
Procedimentos Cirúrgicos do Sistema Digestório , Inibidores do Fator Xa/administração & dosagem , Trato Gastrointestinal/cirurgia , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Rivaroxabana/administração & dosagem , Administração Oral , Adulto , Idoso , Disponibilidade Biológica , Monitoramento de Medicamentos , Inibidores do Fator Xa/sangue , Inibidores do Fator Xa/farmacocinética , Feminino , Absorção Gástrica , Trato Gastrointestinal/metabolismo , Humanos , Absorção Intestinal , Masculino , Pessoa de Meia-Idade , Pirazóis/sangue , Pirazóis/farmacocinética , Piridonas/sangue , Piridonas/farmacocinética , Estudos Retrospectivos , Rivaroxabana/sangue , Rivaroxabana/farmacocinéticaRESUMO
H4pypa is a nonadentate nonmacrocyclic chelator, which previously demonstrated high affinity for scandium-44, lutetium-177, and indium-111. Herein, we report the highly stable binary [Zr(pypa)] complex; the nonradioactive complex was synthesized and characterized in detail using high-resolution electrospray-ionization mass spectroscopy (HR-ESI-MS) and various nuclear magnetic resonance spectroscopies (NMR), which revealed C2v symmetry of the complex. The geometry of [Zr(pypa)] was further detailed via X-ray crystallography and compared with the structure of [Fe(Hpypa)]. Despite a slow complexation rate with an association half-life of 31.4 h at pH 2 and room temperature, the [Zr(pypa)] complex is thermodynamically stable (log KML = 38.92, pZr = 39.4). Radiochemical studies demonstrated quantitative radiolabeling achieved at 10 µM chelator concentration within 2 h at 40 °C and pH = 7, antibody-compatible conditions. Of the utmost importance, [89Zr][Zr(pypa)] is highly kinetically inert upon challenge with excess EDTA and DFO ligands, superior to [89Zr][Zr(DFO)]+, and maintains inertness toward human serum.
Assuntos
Quelantes/química , Complexos de Coordenação/química , Pirazóis/química , Compostos Radiofarmacêuticos/química , Termodinâmica , Zircônio/química , Complexos de Coordenação/sangue , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Humanos , Cinética , Modelos Moleculares , Conformação Molecular , Pirazóis/sangue , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/síntese química , Zircônio/sangueRESUMO
It is unclear whether elderly patients established on direct oral anticoagulants (DOACs) have greater exposure to these drugs, which could subsequently increase their risk of bleeding. We assessed DOAC exposure and factors affecting it in a real-world elderly cohort of patients. For this, 151 medically stable hospital inpatients (76 established on apixaban, 61 on rivaroxaban, 14 on dabigatran) with a median [interquartile range (IQR)] age of 84 (78-89) years were recruited. Patients provided blood samples for measurement of peak and trough plasma DOAC concentrations. There was up to 48-fold and 13-fold variation in trough and peak plasma drug concentrations respectively. A significantly greater proportion of patients on apixaban had peak plasma drug concentrations within the reported ranges compared to those on either rivaroxaban or dabigatran (82·9% vs. 44·3% vs. 64·3% respectively; P < 0·001). A third of the variability in DOAC plasma concentrations was attributed to the influences of DOAC dosage, renal function and gender. To what extent the observed increases in DOAC exposure in the older patients is the cause of their increased risk of bleeding, which could potentially be ameliorated by dosing titration, requires further investigation.
Assuntos
Inibidores do Fator Xa/uso terapêutico , Trombose/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Dabigatrana/sangue , Dabigatrana/uso terapêutico , Monitoramento de Medicamentos , Inibidores do Fator Xa/sangue , Feminino , Hospitalização , Humanos , Masculino , Pirazóis/sangue , Pirazóis/uso terapêutico , Piridonas/sangue , Piridonas/uso terapêutico , Rivaroxabana/sangue , Rivaroxabana/uso terapêutico , Trombose/prevenção & controleRESUMO
PURPOSE: Knowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects. METHODS: 262 blood samples of 29 patients with acute or chronic GvHD who were administered Ruxolitinib during clinical routine were analyzed. A population pharmacokinetic model obtained from myelofibrosis patients was adapted to our population and was used to identify relevant pharmacokinetic properties and covariates on drug exposure. Relationships between Ruxolitinib exposure and adverse events were assessed. RESULTS: Median of individual mean trough serum concentrations was 39.9 ng/mL at 10 mg twice daily (IQR 27.1 ng/mL, range 5.6-99.8 ng/mL). Applying a population pharmacokinetic model revealed that concentrations in our cohort were significantly higher compared to myelofibrosis patients receiving the same daily dose (p < 0.001). Increased Ruxolitinib exposure was caused by a significant reduction in Ruxolitinib clearance by approximately 50%. Additional comedication with at least one strong CYP3A4 or CYP2C9 inhibitor led to a further reduction by 15% (p < 0.05). No other covariate affected pharmacokinetics significantly. Mean trough concentrations of patients requiring dose reduction related to adverse events were significantly elevated (p < 0.05). CONCLUSION: Ruxolitinib exposure is increased in GvHD patients in comparison to myelofibrosis patients due to reduced clearance and comedication with CYP3A4 or CYP2C9 inhibitors. Elevated Ruxolitinib trough concentrations might be a surrogate for toxicity.
Assuntos
Inibidores do Citocromo P-450 CYP2C9/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Interações Medicamentosas , Doença Enxerto-Hospedeiro/tratamento farmacológico , Nitrilas/farmacocinética , Padrões de Prática Médica/estatística & dados numéricos , Mielofibrose Primária/tratamento farmacológico , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Doença Aguda , Adulto , Idoso , Doença Crônica , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP3A/química , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/patologia , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Nitrilas/sangue , Mielofibrose Primária/metabolismo , Mielofibrose Primária/patologia , Prognóstico , Estudos Prospectivos , Pirazóis/administração & dosagem , Pirazóis/sangue , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Distribuição Tecidual , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: Pralsetinib is an FDA-approved oral small-molecule inhibitor for treatment of rearranged during transfection (RET) proto-oncogene fusion-positive non-small cell lung cancer. We investigated how the efflux transporters ABCB1 and ABCG2, the SLCO1A/1B uptake transporters and the drug-metabolizing enzyme CYP3A influence pralsetinib pharmacokinetics. EXPERIMENTAL APPROACH: In vitro, transepithelial pralsetinib transport was assessed. In vivo, pralsetinib (10 mg/kg) was administered orally to relevant genetically modified mouse models. Pralsetinib concentrations in cell medium, plasma samples and organ homogenates were measured using liquid chromatography-tandem mass spectrometry. KEY RESULTS: Pralsetinib was efficiently transported by human (h)ABCB1 and mouse (m)Abcg2, but not hACBG2. In vivo, mAbcb1a/1b markedly and mAbcg2 slightly limited pralsetinib brain penetration (6.3-and 1.8-fold, respectively). Testis distribution showed similar results. Abcb1a/1b;Abcg2-/- mice showed 1.5-fold higher plasma exposure, 23-fold increased brain penetration, and 4-fold reduced recovery of pralsetinib in the small intestinal content. mSlco1a/1b deficiency did not affect pralsetinib oral availability or tissue exposure. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar boosted pralsetinib plasma exposure (1.3-fold) and brain penetration (19.6-fold) in wild-type mice. Additionally, pralsetinib was a modest substrate of mCYP3A, but not of hCYP3A4, which did not noticeably restrict the oral availability or tissue distribution of pralsetinib. CONCLUSIONS AND IMPLICATIONS: SLCO1A/1B and CYP3A4 are unlikely to affect the pharmacokinetics of pralsetinib, but ABCG2 and especially ABCB1 markedly limit its brain and testis penetration, as well as oral availability. These effects are mostly reversed by oral coadministration of the ABCB1/ABCG2 inhibitor elacridar. These insights may be useful in the further clinical development of pralsetinib.