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1.
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
2.
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
3.
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
4.
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
5.
Toxicol Lett ; 311: 11-16, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31026483

RESUMO

4-(Methylnitrosamino)-l-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN), two tobacco specific nitrosamine carcinogens, can form adducts with DNA and proteins via pyridyloxobutylation upon phase I enzyme-mediated bioactivation. Such DNA modifications have been proposed as the root cause to initiate carcinogenesis. Upon hydrolysis, both DNA and protein modifications would release 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB). The released HPB, being tobacco carcinogen specific, has the potential to serve as a surrogate biomarker for both tobacco exposure and carcinogen bioactivation. Because of its easy access, blood is a great source of such investigations with the potential in epidemiological application. HPB quantification from haemoglobin (Hb), however, has been demonstrated with limited success. To further explore this potentially paradigm-shift opportunity, we reported, for the first time, the detection and quantification of HPB from albumin (Alb) adducts formed by the tobacco-specific nitrosamines in mice and in human smokers. The time-course quantitative analysis of HPB from mouse Alb upon NNK exposure suggests that such an Alb adduct is stable. The amounts of HPB from Alb adducts in smoker plasma averaged 1.82 ± 0.19 pg/mg Alb (0.42 to 3.11 pg/mg Alb), which was 36 times the value in nonsmokers (0.05 ± 0.01 pg/mg Alb). Importantly, HPB level from Alb correlated positively with the level of human tobacco exposure estimated by urinary total nicotine equivalent (TNE) (R2 = 0.6170). For comparison, HPB level from Alb was 16.5 times that of Hb (0.12 ± 0.02 pg/mg Hb) in the plasma and red blood cell (RBC) samples of the same smokers. In addition, there was no significant correlation between HPB levels from Hb and TNE (R2 = 0.0719). These data overall suggest that HPB from Alb adducts can serve as a surrogate biomarker to monitor the level of tobacco exposure and carcinogenic nitrosamine bioactivation.


Assuntos
Butanonas/sangue , Nitrosaminas/metabolismo , Piridinas/sangue , Albumina Sérica/metabolismo , Fumar/sangue , Ativação Metabólica , Biomarcadores/sangue , Biomarcadores/urina , Estudos de Casos e Controles , Feminino , Hemoglobinas/metabolismo , Humanos , Modelos Animais , Nicotina/urina , Ligação Proteica , Fumar/efeitos adversos , Fumar/urina , Espectrometria de Massas em Tandem , Fatores de Tempo
6.
Drug Res (Stuttg) ; 69(9): 505-511, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30822797

RESUMO

Ivosidenib is an approved drug for relapsed or refractory IDH1 mutant AML patients. The goal of the present work is to develop and validate an LC-MS/MS method for the quantitation of ivosidenib in mice dried blood spots (DBS) as per regulatory guideline in the linearity range of 1.10-3293 ng/mL. To date there is no bioanalytical method reported for quantitation of ivosidenib. The chromatographic resolution of ivosidenib and internal standard (warfarin) was achieved on a C18 column with an isocratic mobile phase. All validation parameters met the acceptance criteria. The intra- and inter-day precision was in the range of 2.79-10.5 and 5.76-9.02%, respectively. Ivosidenib was stable for 3 freeze/thaw cycles, up to 7 days at room temperature and for one month at -80°C. The applicability of the validated method is shown in a mice pharmacokinetic study. Ivosidenib was quantifiable up to 24 and 36 h following intravenous and oral administration to mice, respectively. The oral bioavailability was 48%. Comparison of DBS vs. plasma concentrations of ivosidenib showed excellent correlation, indicating DBS can be used as an alternative for plasma for pharmacokinetic analysis.


Assuntos
Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Piridinas/sangue , Piridinas/farmacocinética , Animais , Disponibilidade Biológica , Calibragem , Cromatografia Líquida/métodos , Teste em Amostras de Sangue Seco/métodos , Glicina/sangue , Glicina/farmacocinética , Isocitrato Desidrogenase/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
7.
Crit Care ; 23(1): 62, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30795779

RESUMO

There is a high degree of uncertainty regarding optimum care of patients with potential or known intake of oral anticoagulants and traumatic brain injury (TBI). Anticoagulation therapy aggravates the risk of intracerebral hemorrhage but, on the other hand, patients take anticoagulants because of an underlying prothrombotic risk, and this could be increased following trauma. Treatment decisions must be taken with due consideration of both these risks. An interdisciplinary group of Austrian experts was convened to develop recommendations for best clinical practice. The aim was to provide pragmatic, clear, and easy-to-follow clinical guidance for coagulation management in adult patients with TBI and potential or known intake of platelet inhibitors, vitamin K antagonists, or non-vitamin K antagonist oral anticoagulants. Diagnosis, coagulation testing, and reversal of anticoagulation were considered as key steps upon presentation. Post-trauma management (prophylaxis for thromboembolism and resumption of long-term anticoagulation therapy) was also explored. The lack of robust evidence on which to base treatment recommendations highlights the need for randomized controlled trials in this setting.


Assuntos
Anticoagulantes/uso terapêutico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Administração Oral , Anticoagulantes/efeitos adversos , Áustria , Lesões Encefálicas Traumáticas/fisiopatologia , Consenso , Dabigatrana/efeitos adversos , Dabigatrana/uso terapêutico , Desamino Arginina Vasopressina/farmacologia , Humanos , Comunicação Interdisciplinar , Tempo de Tromboplastina Parcial/métodos , Pirazóis/análise , Pirazóis/sangue , Pirazóis/uso terapêutico , Piridinas/análise , Piridinas/sangue , Piridinas/uso terapêutico , Piridonas/análise , Piridonas/sangue , Piridonas/uso terapêutico , Rivaroxabana/análise , Rivaroxabana/sangue , Rivaroxabana/uso terapêutico , Tiazóis/análise , Tiazóis/sangue , Tiazóis/uso terapêutico , Tromboembolia/prevenção & controle , Tomografia Computadorizada por Raios X/métodos , Ácido Tranexâmico/uso terapêutico , Resultado do Tratamento , Vitamina K/antagonistas & inibidores , Vitamina K/uso terapêutico
8.
J Pharm Biomed Anal ; 168: 64-74, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30797103

RESUMO

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


Assuntos
Cromatografia Líquida/métodos , Indazóis/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/farmacocinética , Pirrolidinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Triazóis/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Cães , Feminino , Humanos , Indazóis/administração & dosagem , Indazóis/sangue , Masculino , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Piridinas/administração & dosagem , Piridinas/sangue , Pirrolidinas/administração & dosagem , Pirrolidinas/sangue , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Especificidade da Espécie , Triazóis/administração & dosagem , Triazóis/sangue
9.
Cancer Chemother Pharmacol ; 83(5): 837-848, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30758648

RESUMO

PURPOSE: Pharmacokinetics, absorption, metabolism, and excretion of ivosidenib, a mutant isocitrate dehydrogenase-1 inhibitor, were determined in healthy male subjects. METHODS: In this open-label phase I study, a single dose of [14C]ivosidenib (500 mg, 200 µCi/subject) was orally administered to eight subjects (CYP2D6 extensive, intermediate, or poor metabolizers) under fasted conditions. Blood, plasma, urine, and fecal samples were assayed for radioactivity and profiled for metabolites. Ivosidenib plasma concentrations were determined using LC-MS/MS. Metabolites were separated using reverse-phase HPLC and analyzed using high-resolution LC-MS and LC-MS/MS. RESULTS: Ivosidenib was readily absorbed and slowly eliminated from plasma. Median Tmax of both unchanged ivosidenib and radioactivity in plasma was 4 h. Plasma t½ values for total radioactivity and ivosidenib were 71.7 and 53.4 h, respectively. The mean AUC0-72 blood-to-plasma total radioactivity concentration ratio was 0.565, indicating minimal partitioning to red blood cells. CYP2D6 genotype had no effect on ivosidenib exposure. The mean recovery of radioactivity in excreta was 94.3% over 360 h post-dose; the majority was excreted in feces (77.4 ± 9.62%) with a low percentage recovered in urine (16.9 ± 5.62%), suggesting fecal excretion is the primary route of elimination. Unchanged [14C]ivosidenib accounted for 67.4% of the administered radioactivity in feces. Only [14C]ivosidenib was detected in plasma, representing 92.4% of the total plasma radioactivity. Thirteen metabolites were structurally identified in excreta. CONCLUSION: Ivosidenib was well-absorbed, slowly metabolized to multiple oxidative metabolites, and eliminated by fecal excretion, with no CYP2D6 effect observed. Unchanged ivosidenib was the only circulating species in plasma.


Assuntos
Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Piridinas/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Radioisótopos de Carbono , Cromatografia Líquida , Fezes/química , Glicina/administração & dosagem , Glicina/sangue , Glicina/farmacocinética , Glicina/urina , Voluntários Saudáveis , Humanos , Limite de Detecção , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/sangue , Piridinas/urina , Espectrometria de Massas em Tandem , Distribuição Tecidual
10.
Drug Res (Stuttg) ; 69(6): 342-347, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30658353

RESUMO

A sensitive, specific and cost-effective HPLC method was developed for quantitative determination of carbinoxamine in human plasma using liquid chromatography with ultraviolet detection. A simple liquid-liquid extraction by ethyl acetate was used to extract carbinoxamine from human plasma. Satisfactory separation was achieved by a mobile phase consisting of 20 mM ammonium dihydrogen orthophosphate containing 0.01% triethyl amine (pH adjusted to 3 by using phosphoric acid) and acetonitrile in ratio of (75:25, v/v) at a flow rate of 0.9 mL/min on Hypersil® BDS C18 column (250×4.6 mm, 5 µm) column. The UV detector was set at 260 nm. The developed method was validated in human plasma with a lower limit of quantitation of 5 ng/mL for carbinoxamine. Linearity was demonstrated over the concentration range 5-200 ng/mL. The observed within- and between-day assay precision ranged from 1.902 to 14.90%; accuracy varied between 98.87 and 108.0%. This method can be used suitably for pharmacokinetic studies and in therapeutic drug monitoring in patients treated with carbinoxamine.


Assuntos
Monitoramento de Medicamentos/métodos , Antagonistas dos Receptores Histamínicos H1/sangue , Extração Líquido-Líquido/métodos , Piridinas/sangue , Administração Oral , Adolescente , Cromatografia Líquida de Alta Pressão/economia , Cromatografia Líquida de Alta Pressão/métodos , Análise Custo-Benefício , Monitoramento de Medicamentos/economia , Estudos de Viabilidade , Voluntários Saudáveis , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Humanos , Limite de Detecção , Extração Líquido-Líquido/economia , Masculino , Piridinas/administração & dosagem , Piridinas/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrofotometria Ultravioleta , Adulto Jovem
11.
Artigo em Inglês | MEDLINE | ID: mdl-30660839

RESUMO

Hepatocellular carcinoma (HCC) is a fatal oncogenic disorder with few therapeutic options. Novel therapeutic strategy with combination of a selective CDK4/6 inhibitor palbociclib (PAL) with a tyrosine kinase inhibitor (TKI) sorafenib (SOR) is reported to impair tumour growth and significantly increased survival in various preclinical models of HCC. In the current work a sensitive and rapid UHPLC-QTOF-MS method was established for the concurrent quantification of PAL and SOR in rat plasma using ibrutinib as internal standard (IS). Chromatographic separation was carried out on an Agilent Poroshell EC C18 (50 mm × 3 mm, 2.7 µm) using gradient mobile phase consisting of 0.1% formic acid and acetonitrile. Flow rate of 0. 45 mL/min with a run time of 5 min was used for separation. A simple sample preparation approach of protein precipitation was used in the current study. The mass spectrometric analysis of selective ions at [M + H]+m/z 448.2455 for PAL, m/z 465.0936 for SOR and m/z 441.2034 for IS was monitored with extracted ion chromatography. The LC-MS method meets the regulatory bio-analytical guidelines, exhibited good sensitivity and linearity over the range of 1.0-2000.0 ng/mL for PAL and SOR. The pharmacokinetic parameters of PAL remained unchanged when SOR was co-administered with PAL. The study pointed out that the co-intake of PAL with SOR resulted in a slight increment of Cmax (11.21%) and AUC (7.95%) levels of SOR when co-administered with PAL when compared to individual oral intake in SD rats. The current method provides a modern rapid and sensitive tool for pharmacokinetic studies of PAL and SOR in a pre-clinical set up.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Piperazinas/farmacocinética , Piridinas/farmacocinética , Sorafenibe/farmacocinética , Animais , Carcinoma Hepatocelular/sangue , Cromatografia Líquida de Alta Pressão , Quimioterapia Combinada , Masculino , Piperazinas/sangue , Pirazóis , Piridinas/sangue , Pirimidinas , Ratos , Ratos Sprague-Dawley , Sorafenibe/sangue , Espectrometria de Massas em Tandem
12.
Biomed Chromatogr ; 33(2): e4388, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30238481

RESUMO

In this study, we developed a method for the determination of Penicillium griseofulvum-oriented pyripyropene A (PPPA), a selective inhibitor of acyl-coenzyme A:cholesterol acyltransferase 2, in mouse and human plasma and validated it using liquid chromatography-tandem mass spectrometry. Pyripyropene A (PPPA) and an internal standard, carbamazepine, were separated using a Xterra MS C18 column with a mixture of acetonitrile and 0.1% formic acid as the mobile phase. The ion transitions monitored in positive-ion mode [M + H]+ of multiple-reaction monitoring (MRM) were m/z 148.0 from m/z 584.0 for PPPA and m/z 194.0 from m/z 237.0 for the internal standard. The detector response was specific and linear for PPPA at concentrations within the range from 1 to 5,000 ng/mL. The intra-/inter-day precision and accuracy of the method was acceptable by the criteria for assay validation. The matrix effects of PPPA ranged from 97.6 to 104.2% and from 93.3 to 105.3% in post-preparative mouse and human plasma samples, respectively. PPPA was also stable under various processing and/or handling conditions. Finally, PPPA concentrations in the mouse plasma samples could be measured after intravenous, intraperitoneal, or oral administration of PPPA, suggesting that the assay is useful for pharmacokinetic studies on mice and applicable to human studies.


Assuntos
Cromatografia Líquida/métodos , Penicillium/química , Piridinas/sangue , Piridinas/farmacocinética , Sesquiterpenos/sangue , Sesquiterpenos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Modelos Lineares , Masculino , Camundongos , Camundongos Endogâmicos ICR , Piridinas/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sesquiterpenos/química , Esterol O-Aciltransferase/antagonistas & inibidores
13.
Xenobiotica ; 49(8): 953-960, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30215545

RESUMO

1. Leniolisib is a novel oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor, currently in clinical development for the treatment of inflammatory and autoimmune diseases. 2. We investigated the absorption, metabolism, and excretion of leniolisib in healthy subjects after a single oral 400 mg dose as part of a first-in-human clinical study. The parent drug and metabolites were quantified by 19F-NMR in plasma, urine and faeces after liquid chromatography separation, and structures were determined by liquid chromatography coupled to tandem mass spectrometry. 3. Drug-related material was mainly excreted as oxidative metabolites in urine and faeces, providing evidence that elimination occurs mainly by metabolism. No metabolites were abundant in plasma relative to the parent drug. An average mass balance of 66% was obtained, demonstrating that relatively extensive elimination/excretion data can be obtained by 19F-NMR in a first in human clinical study without the use of a radiolabeled drug.


Assuntos
Absorção Fisiológica , Flúor/química , Voluntários Saudáveis , Espectroscopia de Ressonância Magnética , Inibidores de Proteínas Quinases/metabolismo , Piridinas/metabolismo , Pirimidinas/metabolismo , Administração Oral , Adolescente , Adulto , Fezes , Feminino , Humanos , Masculino , Metaboloma , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/urina , Piridinas/sangue , Piridinas/farmacocinética , Piridinas/urina , Pirimidinas/sangue , Pirimidinas/farmacocinética , Pirimidinas/urina , Adulto Jovem
14.
Xenobiotica ; 49(9): 1001-1006, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30216091

RESUMO

Steady-state plasma concentrations of anticoagulants and the time since the previous administration in mainly outpatients with atrial fibrillation administered standard or reduced doses were analyzed for 110 elderly Japanese subjects (mean age, 76 years) treated with apixaban (2.5 or 5.0 mg twice daily), dabigatran etexilate (110 or 150 mg twice daily), edoxaban (30 or 60 mg once daily) or rivaroxaban (10 or 15 mg once daily) at one general hospital. The pharmacokinetics in patients treated with standard and reduced doses of the four anticoagulants using liquid chromatography-tandem mass spectrometry was compared with the concentration ranges estimated using physiologically based pharmacokinetic modeling. Reduced doses of anticoagulants resulted in relatively small pharmacokinetic variations compared with the standard dose. Statistical analyses revealed that renal impairment is likely not the sole determinant factor for high plasma concentrations of apixaban, dabigatran, edoxaban and rivaroxaban. Patients with atrial fibrillation should be treated with the correct doses of oral anticoagulants as specified in the package inserts (e.g. reduced doses for elderly patients, patients with low body weights and in combination with P-glycoprotein inhibitor drugs) to avoid excessive or insufficient doses of direct oral anticoagulants.


Assuntos
Anticoagulantes/sangue , Anticoagulantes/farmacocinética , Fibrilação Atrial/tratamento farmacológico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Dabigatrana/administração & dosagem , Dabigatrana/efeitos adversos , Dabigatrana/sangue , Dabigatrana/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Nefropatias/induzido quimicamente , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirazóis/sangue , Pirazóis/farmacocinética , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/sangue , Piridinas/farmacocinética , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Piridonas/sangue , Piridonas/farmacocinética , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Rivaroxabana/sangue , Rivaroxabana/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Tiazóis/sangue , Tiazóis/farmacocinética
15.
Transpl Infect Dis ; 21(1): e13007, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30295407

RESUMO

INTRODUCTION: Isavuconazole, a triazole antifungal, is an inhibitor of cytochrome P450 3A4, which also metabolizes tacrolimus and sirolimus. In previous studies, isavuconazole administration increased tacrolimus and sirolimus area under the curve values by 2.3-fold and 1.8-fold, respectively, in healthy adults and tacrolimus concentration/dose (C/D) ratio by 1.3-fold in solid organ transplant patients. We aimed to determine the magnitude of effect of isavuconazole administration on tacrolimus and sirolimus C/D ratios in allogeneic hematopoietic stem cell transplant (alloHSCT) patients. METHODS: A retrospective, single-center, single-arm study in adult alloHSCT patients who received at least 10 days of combination therapy with isavuconazole and tacrolimus and/or sirolimus as inpatients or outpatients was conducted. Tacrolimus and sirolimus trough serum concentrations were measured up to twice weekly for up to 4 weeks. RESULTS: Twenty-two patients receiving tacrolimus and twenty patients receiving sirolimus met the inclusion criteria. The mean C/D ratio increased from baseline by 1.42-fold for tacrolimus during week 1 (P = 0.002) and up to 1.56-fold for sirolimus during week 2 (P = 0.02). For the remaining timepoints, tacrolimus and sirolimus C/D ratios were not statistically significantly different from baseline. CONCLUSION: In alloHSCT patients, modest increases in tacrolimus and sirolimus C/D ratios from baseline were observed within the first 2 weeks after initiation of isavuconazole.


Assuntos
Antifúngicos/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/farmacologia , Adulto , Idoso , Antifúngicos/uso terapêutico , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/sangue , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Interações de Medicamentos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nitrilos/sangue , Nitrilos/farmacologia , Nitrilos/uso terapêutico , Piridinas/sangue , Piridinas/farmacologia , Piridinas/uso terapêutico , Estudos Retrospectivos , Sirolimo/sangue , Sirolimo/metabolismo , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Tacrolimo/sangue , Tacrolimo/metabolismo , Tacrolimo/farmacologia , Tacrolimo/uso terapêutico , Transplante Homólogo/efeitos adversos , Triazóis/sangue , Triazóis/farmacologia , Triazóis/uso terapêutico , Adulto Jovem
16.
Cancer Chemother Pharmacol ; 83(1): 107-113, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30368586

RESUMO

PURPOSE: The ability of predicting severe adverse reactions caused by regorafenib is important. We evaluated regorafenib concentrations for adverse reaction risks and assessed the relevance of laboratory values and gene polymorphisms. METHODS: A total of 28 Japanese cancer patients who were treated with regorafenib were evaluated for the steady state of serum regorafenib concentrations and adverse reactions for 28 days. In addition, we determined the association of regorafenib concentrations with ABCG2 and OATP1B1 polymorphisms, which are regorafenib transporters. RESULTS: Regorafenib concentrations were significantly higher in the group with Grade 2 or higher total bilirubin elevation and thrombocytopenia compared with the group with grades 0 or 1 [3.45 (2.18-7.31) vs. 1.76 (0.26-2.77) µg/mL, P = 0.01 and 3.45 (2.12-7.31) vs. 1.76 (0.26-2.77) µg/mL, P = 0.02, respectively]. A strong association was noted between serum regorafenib concentrations and total bilirubin levels, but the physical and genetic factors predicting regorafenib pharmacokinetics could not be clarified. CONCLUSIONS: Regorafenib concentrations were associated with total bilirubin elevation and thrombocytopenia. Total serum bilirubin could be a useful marker when estimating regorafenib pharmacokinetics.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Neoplasias do Colo/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Proteínas de Neoplasias/genética , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/sangue , Polimorfismo Genético , Piridinas/efeitos adversos , Piridinas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Feminino , Seguimentos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
17.
Biomed Chromatogr ; 33(4): e4469, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30549069

RESUMO

Green tea extracts (GTE) has been reported to be a kinase inhibitor and modulator for various drug metabolizing enzymes. It may give synergetic antioncogenic effect, but with a possibility of pharmacokinetic interactions with various co-administered anticancer agents like palbociclib (PAL), a selective inhibitor of CDK-4/6 primarily metabolized by CYP3A enzyme. To explore the impact of GTE on PAL pharmacokinetics in Sprague-Dawley rats, a rapid and sensitive UHPLC-QTOF-MS method was established. Chromatographic separation was carried out on an Acquity UPLC BEH C18 (100 × 2.1 mm, 1.7 µm) column using a gradient mobile phase system consisting of 0.1% formic acid and acetonitrile. Sample preparation was based on a simple protein precipitation method. Estimation of target ions [M + H]+ at m/z 448.2455 for PAL and m/z 441.2044 for ibrutinib (IS) was performed in selective ion mode ESI-HRMS. Good sensitivity (1.0 ng/mL) and linearity over a wide concentration range of 1-2000 ng/mL was exhibited by the method. The results indicated that the administration of GTE resulted in decreased oral bioavailability of PAL in both short- and long-term conditions. However, when both conditions were compared, the variation was less for the peak concentration and area under the concentration-time curve level of PAL.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Interações Ervas-Drogas , Piperazinas , Extratos Vegetais/farmacologia , Piridinas , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Chá/química , Animais , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Masculino , Piperazinas/sangue , Piperazinas/química , Piperazinas/farmacocinética , Piridinas/sangue , Piridinas/química , Piridinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
18.
Jpn J Clin Oncol ; 49(2): 121-129, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30576544

RESUMO

Objective: Netupitant is a novel, selective neurokinin-1 receptor antagonist used for prevention of chemotherapy-induced nausea and vomiting, a distressing side effect of chemotherapy. This double-blind, randomized, Phase II study investigated the dose-response of oral netupitant in Japanese patients receiving highly emetogenic chemotherapy. Methods: Chemotherapy-naïve patients were randomized (1:1:1) to a single oral netupitant 30-, 100- or 300-mg dose before chemotherapy initiation. Patients received concomitant palonosetron (0.75 mg intravenously [i.v.] Day 1) and dexamethasone (9.9 mg i.v. Day 1, 8 mg orally Days 2-4). Results: Overall, 402 patients (30 mg: 134; 100 mg: 135; 300 mg: 133) were treated and evaluable for efficacy and safety. The primary endpoint of overall (0-120 h after chemotherapy administration) complete response (CR) rate (no emesis, no rescue medication) was 64.2%, 60.0% and 54.9% in the 30-, 100- and 300-mg arms, respectively, without statistical significance for dose-response. The safety profile of netupitant was comparable in the three arms. The plasma concentrations of netupitant and its metabolites increased with the dose increase from 30 mg to 300 mg. Conclusions: No dose-response relationship of netupitant in terms of overall CR rate was observed in this study. Netupitant was well tolerated at all doses without clinically harmful safety signals observed. Clinical trial registration: JapicCTI-142 483.


Assuntos
Antineoplásicos/efeitos adversos , Eméticos/efeitos adversos , Náusea/tratamento farmacológico , Palonossetrom/administração & dosagem , Palonossetrom/uso terapêutico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Vômito/tratamento farmacológico , Administração Oral , Adulto , Idoso , Aminas , Antieméticos/administração & dosagem , Antieméticos/uso terapêutico , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Náusea/sangue , Náusea/induzido quimicamente , Náusea/prevenção & controle , Palonossetrom/sangue , Palonossetrom/farmacocinética , Piridinas/sangue , Piridinas/farmacocinética , Resultado do Tratamento , Vômito/sangue , Vômito/induzido quimicamente , Vômito/prevenção & controle
19.
J Infect Dis ; 219(7): 1026-1034, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30428049

RESUMO

BACKGROUND: Pimodivir, a first-in-class inhibitor of influenza virus polymerase basic protein 2, is being developed for hospitalized and high-risk patients with influenza A. METHODS: In this double-blinded phase 2b study, adults with acute uncomplicated influenza A were randomized 1:1:1:1 to receive one of the following treatments twice daily for 5 days: placebo, pimodivir 300 mg or 600 mg, or pimodivir 600 mg plus oseltamivir 75 mg. Antiviral activity, safety, and pharmacokinetics of pimodivir alone or in combination were evaluated. RESULTS: Of 292 patients randomized, 223 were treated and had confirmed influenza A virus infection. The trial was stopped early because the primary end point was met; the area under the curve of the viral load, determined by quantitative reverse transcription-polymerase chain reaction analysis, in nasal secretions from baseline to day 8 significantly decreased in the active treatment groups, compared with the placebo group (300 mg group, -3.6 day*log10 copies/mL [95% confidence interval {CI}, -7.1 to -0.1]; 600 mg group, -4.5 [95%CI -8.0 to -1.0]; and combination group, -8.6 [95% CI, -12.0 to -5.1]). Pimodivir plus oseltamivir yielded a significantly lower viral load titer over time than placebo and a trend for a shorter time to symptom resolution than placebo. Pimodivir plasma concentrations increased in a dose-proportional manner. The most commonly reported adverse event was mild or moderate diarrhea. CONCLUSIONS: Pimodivir (with or without oseltamivir) resulted in significant virologic improvements over placebo, demonstrated trends in clinical improvement, and was well tolerated. Pimodivir 600 mg twice daily is in further development. CLINICAL TRIALS REGISTRATION: NCT02342249, 2014-004068-39, and CR107745.


Assuntos
Antivirais/uso terapêutico , Vírus da Influenza A , Influenza Humana/tratamento farmacológico , Oseltamivir/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Doença Aguda , Adulto , Antivirais/efeitos adversos , Antivirais/sangue , Antivirais/farmacocinética , Diarreia/induzido quimicamente , Método Duplo-Cego , Farmacorresistência Viral/genética , Quimioterapia Combinada , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Vírus da Influenza A/genética , Vírus da Influenza A/fisiologia , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Oseltamivir/sangue , Piridinas/efeitos adversos , Piridinas/sangue , Piridinas/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/sangue , Pirimidinas/farmacocinética , Pirróis/efeitos adversos , Pirróis/sangue , Pirróis/farmacocinética , Fatores de Tempo , Carga Viral , Proteínas Virais/genética , Eliminação de Partículas Virais
20.
J Pharm Biomed Anal ; 164: 725-733, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30472591

RESUMO

Cligosiban is a highly-affinity nonpeptide oxytocin receptor antagonist. In this study, a simple an sensitive LC-MS/MS method was developed and validated for the determination of cligosiban in rat plasma. The plasma samples were pretreated with acetonitrile as precipitant and then separated on an ACQUITY BEH C18 column (2.1 × 50 mm, 1.7 µm) with 0.1% formic acid in water and acetonitrile as mobile phase. The analytes were monitored using selected reaction monitoring (SRM) mode with transitions at m/z 420.1→248.1 for cligosiban and m/z 304.1→161.1 for IS. The developed method showed good linearity over the concentration range of 1-1000 ng/mL with coefficient of correlation > 0.996. The lower limit of quantification (LLOQ) is 1 ng/mL. The method was validated for selectivity, precision, accuracy, recovery, and stability in accordance with FDA's guidance. The validated assay has been successfully applied to the pharmacokinetic study of cligosiban in rat plasma after intravenous and oral administration. According to the current results, the oral bioavailability of cligosiban was 63.82%. Furthermore, the metabolites present in rat liver microsomes (RLM), human liver microsomes (HLM) and rat plasma were analyzed by UHPLC-LTQ-Orbitrap-MS method, and four metabolites structurally identified based on their accurate masses, and fragment ions. The proposed metabolic pathways of cligosiban were demethylation and glucuronidation. This study is the first report on the pharmacokinetic and metabolic information of cligosiban, which would provide insights into the effectiveness and toxicity of cligosiban.


Assuntos
Antagonistas de Hormônios/farmacocinética , Piridinas/farmacocinética , Receptores de Ocitocina/antagonistas & inibidores , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Triazóis/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão/métodos , Desmetilação , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/sangue , Humanos , Masculino , Microssomos Hepáticos , Piridinas/administração & dosagem , Piridinas/sangue , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Triazóis/administração & dosagem , Triazóis/sangue
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