Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 346
Filtrar
1.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1122-1123: 58-63, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31153132

RESUMO

Imrecoxib is a specific inhibitor of cyclooxygenase-2. Its hydroxymethyl (M1) and carboxylic acid (M2) metabolites are the major circulating components in human plasma. It has been demonstrated that the anti-inflammatory activities of M1 and M2 are both equal to the parent drug. In the current study, a highly sensitive and rapid method was established and validated for the determination of imrecoxib, M1 and M2 in human plasma via liquid chromatography-tandem mass spectrometry technique. To our knowledge, this is the first study that simultaneously analyzed imrecoxib and its two active metabolites following a rapid protein-precipitation clean-up. Imrecoxib and its metabolites were separated on a reversed-C18 column (3.5 µm; 100 × 4.6 mm), and the mobile phase was optimized as 5 mM ammonium acetate: acetonitrile: formic acid (35: 65: 0.1, v/v/v), based on the pKa values of analytes. Mass spectrometric detection was conducted in a positive multiple reaction monitoring mode. The m/z transitions of imrecoxib (370.2 → 278.2), M1 (386.2 → 278.2) and M2 (400.2 → 236.2) were selected for an effective balance between sensitivity and selectivity. An excellent linearity was demonstrated over the concentration ranges of 0.100-40.0, 0.200-80.0 and 2.00-800 ng/mL for imrecoxib, M1 and M2, respectively. The method validation was carried out in agreement with the FDA guidance. Furthermore, the pharmacokinetic properties of imrecoxib and its two active metabolites were characterized in patients with moderate hepatic impairment, by using the developed and validated method.


Assuntos
Cromatografia Líquida/métodos , Pirróis , Sulfetos , Espectrometria de Massas em Tandem/métodos , Humanos , Limite de Detecção , Modelos Lineares , Hepatopatias , Pirróis/sangue , Pirróis/química , Pirróis/farmacocinética , Reprodutibilidade dos Testes , Sulfetos/sangue , Sulfetos/química , Sulfetos/farmacocinética
2.
Eur J Clin Pharmacol ; 75(10): 1355-1360, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31243478

RESUMO

OBJECTIVE: Renal insufficiency may influence the pharmacokinetics of drugs. We have investigated the pharmacokinetic parameters of imrecoxib and its two main metabolites in individuals with osteoarthritis (OA) with normal renal function and renal insufficiency, respectively. METHODS: This was a prospective, parallel, open, matched-group study in which 24 subjects were enrolled (renal insufficiency group, n = 12; healthy control group, n = 12). Blood samples of subjects administered 100 mg imrecoxib were collected at different time points and analyzed. Plasma concentrations of imrecoxib and its two metabolites (M1 and M2) were determined by the liquid chromatography-tandem mass spectrometry method, and pharmacokinetic parameters (clearance [CL], apparent volume of distribution [Vd], maximum (or peak) serum concentration [Cmax], amount of time drug is present in serum at Cmax [Tmax], area under the curve [AUC; total drug exposure across time], mean residence time [MRT] and elimination half-life [t1/2]) were calculated. RESULTS: The demographic characteristics of the two groups were not significantly different, with the exception of renal function. The mean Cmax and AUC0-t (AUC from time 0 to the last measurable concentration) of imrecoxib in the renal insufficiency group were 59 and 70%, respectively, of those of the healthy control volunteers with normal renal function, indicating a significant decline in the former group (P < 0. 05). The mean pharmacokinetic parameters of Ml in the renal insufficiency and healthy control groups did not significantly differ. In contrast, the mean Cmax and AUC0-t of M2 in the renal insufficiency group were 233 and 367%, respectively, of those of the normal renal function group, indicating a significant increase in the former group (P < 0.05). The mean CL/F (clearance/bioavailability) of M2 of the renal insufficiency group was 37% of that of the normal renal function group, indicating a notable reduction in the former group (P < 0.05). CONCLUSION: The exposure of imrecoxib in OA patients with renal insufficiency showed a decline compared to that in healthy subjects. However, in patients with renal insufficiency the exposure of M2 was markedly increased and the CL was noticeably reduced. These results indicate that the dosage of imrecoxib should be reduced appropriately in patients with renal insufficiency.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacocinética , Pirróis/farmacocinética , Insuficiência Renal/metabolismo , Sulfetos/farmacocinética , Adulto , Idoso , Inibidores de Ciclo-Oxigenase 2/sangue , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Interações de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Pirróis/sangue , Pirróis/uso terapêutico , Insuficiência Renal/tratamento farmacológico , Sulfetos/sangue , Sulfetos/uso terapêutico
3.
Int Arch Occup Environ Health ; 92(6): 873-881, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30955093

RESUMO

OBJECTIVES: Urinary excretion of 2,5-hexanedione is currently used to estimate the exposure levels of hexane occurring to an individual during the previous work shift. However, because hexane exposures and urinary 2,5-hexanedione levels can vary considerably from day to day, and subchronic to chronic exposures to hexane are required to produce neuropathy, this biomarker may not accurately reflect the risk of an individual for developing hexane neuropathy. This investigation examines the potential of hexane-derived pyrrole adducts produced on globin and plasma proteins as markers for integrating cumulative exposures. Because the pyrrole markers incorporate bioactivation of hexane to 2,5-hexandione and the initial step of protein adduction involved in hexane-induced neuropathy, they potentially can serve as biomarkers of effect through reflecting pathogenetic events within the nervous system. Additionally, pyrrole formation is an irreversible reaction suggesting that hexane-derived protein pyrroles can be used to assess cumulative exposures to provide a better characterization of individual susceptibilities. METHODS: To examine the utility of the proposed markers, blood samples were obtained from eleven workers who used hexane for granulating metal powders in a slurry to produce metal machining die tools and four non-exposed volunteers. Globin and plasma were isolated, and the proteins were digested using pepsin, reacted with Ehrlich's reagent and the level of pyrrole adducts were determined by absorbance at 530 nm. To determine the dose-response curve and dynamic range of the assay, erythrocytes were incubated with a range of 2,5-hexanedione concentrations and the net absorbance at 530 nm of isolated globin was measured. RESULTS: Pyrrole was detected in both the globin and plasma samples of the workers exposed to hexane and the levels of pyrroles in plasma were positively correlated with the levels of pyrroles in globin for most of the workers. CONCLUSIONS: This investigation demonstrates that detectable levels of hexane-derived protein pyrrole adducts are produced on peripheral proteins following occupational exposures to hexane and supports the utility of measuring pyrroles for integrating cumulative exposures to hexane.


Assuntos
Globinas/metabolismo , Hexanos/metabolismo , Plasma/química , Pirróis/sangue , Biomarcadores/sangue , Globinas/química , Humanos , Exposição Ocupacional/efeitos adversos , Pirróis/metabolismo
4.
Drug Res (Stuttg) ; 69(6): 330-336, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30193392

RESUMO

A simple, sensitive and rapid assay method has been developed and validated as per regulatory guideline for the estimation of tofacitinib on mice dried blood spots (DBS) using liquid chromatography coupled to tandem mass spectrometry with electro spray ionization in the positive-ion mode. The method employs liquid extraction of tofacitinib from DBS disk of mice whole blood followed by chromatographic separation using 5 mM ammonium acetate (pH 6.5):acetonitrile (20:80, v/v) at a flow rate of 0.60 mL/min on an X-Terra Phenyl column with a total run time 2.5 min. The MS/MS ion transitions monitored were m/z 313→149 for tofacitinib and m/z 316→149 for the internal standard (13C3, 15N-tofacitinib). The assay was linear in the range of 0.99-1980 ng/mL. The intra- and inter-day precision was in the range of 1.17-10.3 and 3.37-10.9%, respectively. Stability studies showed that tofacitinib was stable on DBS cards for one month. This novel method has been applied to analyze the DBS samples of tofacitinib obtained from a pharmacokinetic study in mice.


Assuntos
Teste em Amostras de Sangue Seco/métodos , Piperidinas/sangue , Inibidores de Proteínas Quinases/sangue , Pirimidinas/sangue , Pirróis/sangue , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Injeções Intravenosas , Janus Quinase 3/antagonistas & inibidores , Masculino , Camundongos , Modelos Animais , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Pirróis/administração & dosagem , Pirróis/farmacocinética , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos
5.
Biomed Chromatogr ; 33(4): e4458, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30520053

RESUMO

A highly sensitive, selective and rapid ultra-performance liquid chromatography-tandem mass spectrometry method has been developed for the quantification of a Janus kinase (JAK) inhibitor, tofacitinib (TOF). The assay employed liquid-liquid extraction with methyl-tert butyl ether to extract tofacitinib and tofacitinib-13C3 15 N (as internal standard) from human plasma. The samples were analyzed on a UPLC BEH C18 (50 × 2.1 mm, 1.7 µm) column using acetonitrile and 10.0 mm ammonium acetate, pH 4.5 (75:25, v/v) as the mobile phase within 1.4 min. The precursor/product ion transitions were monitored at m/z 313.3/149.2 and 317.4/149.2 for tofacitinib and tofacitinib-13C3 15 N, respectively, in the positive electrospray ionization mode. The calibration curves were linear (r2  ≥ 0.9978) across the concentration range of 0.05-100 ng/mL. The mean extraction recovery of tofacitinib across quality controls was 98.6%. The intra- and inter-batch precision (CV) and accuracy ranged from 2.1-5.1 and 96.2-103.1%, respectively. All validation results complied well with the current guidelines. The method is amenable to high sample throughput and was applied to determine TOF plasma concentration in a pharmacokinetic study with 12 healthy Indian subjects after oral administration of 5 mg tablets.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Piperidinas/sangue , Pirimidinas/sangue , Pirróis/sangue , Espectrometria de Massas em Tandem/métodos , Adulto , Estabilidade de Medicamentos , Humanos , Modelos Lineares , Extração Líquido-Líquido , Masculino , Pessoa de Meia-Idade , Piperidinas/química , Piperidinas/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Pirróis/química , Pirróis/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
6.
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
7.
Biomed Chromatogr ; 33(2): e4407, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30315654

RESUMO

Sunitinib is an orally administered tyrosine kinase inhibitor. Therapeutic drug monitoring is an important component of the follow-up of patients because of high interpatient variability in the pharmacokinetics of sunitinib and large variabilities in its efficacy and toxicity. The aim of the present study was to examine the light stability of sunitinib and confirm the effects of light exposure on sunitinib measurements by LC-MS/MS. Sunitinib and its active metabolite, SU12662, convert Z isomers to E isomers with exposure to light. The Z-E photoisomerization ratio reached a plateau at 35% for both E isomers in methanol within 15 min of normal light exposure (700 lx). However, the Z isomer of the sunitinib and SU12662 peak area ratios in plasma decreased by 10% within 15 min. These results suggest that sunitinib samples need to be handled without light exposure in all sample preparation steps. Alternatively, it should be measured sunitinib and SU12662 after the sample has reached photoisomerical equilibrium. These results suggest that the sunitinib therapeutic range changes depending on light conditions during sample handling in sunitinib and SU12662 measurements.


Assuntos
Cromatografia Líquida/métodos , Sunitinibe , Espectrometria de Massas em Tandem/métodos , Monitoramento de Medicamentos , Estabilidade de Medicamentos , Humanos , Indóis/sangue , Indóis/química , Indóis/efeitos da radiação , Processos Fotoquímicos , Pirróis/sangue , Pirróis/química , Pirróis/efeitos da radiação , Sunitinibe/sangue , Sunitinibe/química , Sunitinibe/efeitos da radiação
8.
Cancer Chemother Pharmacol ; 82(6): 1067-1080, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30306263

RESUMO

PURPOSE: Metarrestin is a first-in-class small molecule clinical candidate capable of disrupting the perinucleolar compartment, a subnuclear structure unique to metastatic cancer cells. This study aims to define the pharmacokinetic (PK) profile of metarrestin and the pharmacokinetic/pharmacodynamic relationship of metarrestin-regulated markers. METHODS: PK studies included the administration of single or multiple dose of metarrestin at 3, 10, or 25 mg/kg via intravenous (IV) injection, gavage (PO) or with chow to wild-type C57BL/6 mice and KPC mice bearing autochthonous pancreatic tumors. Metarrestin concentrations were analyzed by UPLC-MS/MS. Pharmacodynamic assays included mRNA expression profiling by RNA-seq and qRT-PCR for KPC mice. RESULTS: Metarrestin had a moderate plasma clearance of 48 mL/min/kg and a large volume of distribution of 17 L/kg at 3 mg/kg IV in C57BL/6 mice. The oral bioavailability after single-dose (SD) treatment was > 80%. In KPC mice treated with SD 25 mg/kg PO, plasma AUC0-∞ of 14400 ng h/mL, Cmax of 810 ng/mL and half-life (t1/2) of 8.5 h were observed. At 24 h after SD of 25 mg/kg PO, the intratumor concentration of metarrestin was high with a mean value of 6.2 µg/g tissue (or 13 µM), well above the cell-based IC50 of 0.4 µM. At multiple dose (MD) 25 mg/kg/day PO in KPC mice, mean tissue/plasma AUC0-24h ratio for tumor, spleen and liver was 37, 30 and 31, respectively. There was a good linear relationship of dosage to AUC0-24h and C24h. AUC0-24h MD to AUC0-24h SD ratios ranged from two for liver to five for tumor indicating additional accumulation in tumors. Dose-dependent normalization of FOXA1 and FOXO6 mRNA expression was observed in KPC tumors. CONCLUSIONS: Metarrestin is an effective therapeutic candidate with a favorable PK profile achieving excellent intratumor tissue levels in a disease with known poor drug delivery.


Assuntos
Antineoplásicos/farmacocinética , Organelas/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Pirimidinas/farmacocinética , Pirróis/farmacocinética , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Área Sob a Curva , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Fatores de Transcrição Forkhead/genética , Meia-Vida , Fator 3-alfa Nuclear de Hepatócito/genética , Humanos , Injeções Intravenosas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Especificidade de Órgãos , Organelas/metabolismo , Organelas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Pirimidinas/uso terapêutico , Pirróis/administração & dosagem , Pirróis/sangue , Pirróis/uso terapêutico , Distribuição Tecidual
9.
Artigo em Inglês | MEDLINE | ID: mdl-30150474

RESUMO

A fast and easy-to-use liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination and quantification of a novel antifungal drug, olorofim (F901318), a member of the novel class of orotomides, in human plasma and serum was developed and validated. Sample preparation was based on protein precipitation with acetonitrile and subsequent centrifugation. An isotope-labeled analogue of F901318 was employed as an internal standard. Chromatographic separation was achieved using a 50-mm by 2.1-mm, 1.9-µm, polar Hypersil Gold C18 column and isocratic mobile phase consisting of 0.1% formic acid-acetonitrile (60%-40%, vol/vol) at a flow rate of 330 µl/min. The analyte was detected using a triple-stage quadrupole mass spectrometer operated in selected reaction monitoring (SRM) mode with positive heated electrospray ionization (HESI+) within a single runtime of 2.00 min. The present LC-MS/MS method was validated according to the international guidelines of the International Conference on Harmonisation (ICH) and the U.S. Food and Drug Administration (FDA). Linearity of F901318 concentration ranges was verified by the Mandel test. The calibration curve was tested linear across the range and fitted using least-squares regression with a weighting factor of the reciprocal concentration. The limit of detection was 0.0011 mg/liter, and the lower limit of quantitation was 0.0033 mg/liter. Intraday and interday precisions ranged from 1.17% to 3.23% for F901318, and intraday and interday accuracies (percent bias) ranged from 0.75% to 5.01%. In conclusion, a method was established for the rapid quantitation of F901318 concentrations in serum and plasma samples in patient trials, and it optimizes therapeutic drug monitoring in applying an easy-to-use single method.


Assuntos
Acetamidas/sangue , Antifúngicos/sangue , Cromatografia Líquida/métodos , Piperazinas/sangue , Plasma/química , Pirimidinas/sangue , Pirróis/sangue , Espectrometria de Massas em Tandem/métodos , Acetonitrilos/sangue , Calibragem , Monitoramento de Medicamentos/métodos , Humanos , Limite de Detecção , Reprodutibilidade dos Testes
10.
J Pharm Biomed Anal ; 160: 360-367, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30119000

RESUMO

Sunitinib malate, an oral multi-targeted tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma, gastrointestinal stromal tumor, and well-differentiated pancreatic neuroendocrine tumors, has been identified as a potential candidate for therapeutic drug monitoring approach. Nevertheless, the development of an analytical assay suitable for clinical application for the quantification of the plasma concentration of sunitinib and its active metabolite, N-desethyl sunitinib, is limited by its Z/E isomerization when exposed to light. Several LC-MS/MS methods already published require protection from light during all sample handling procedures to avoid the formation of E-isomer, which makes them not suitable for clinical practice. In order to obtain a simple and fast procedure to reconvert the E-isomer, formed during sample collection and treatment without light protection, and, thus, to have only Z-isomer peak to quantify, we studied the Z/E photodegradation with special attention to the condition allowing the reverse reaction in plasma matrix. After 30 min of light exposure, the E-isomer maximum percentage of both the analytes was reached (44% of E-sunitinib and 20% of E-N-desethyl sunitinib; these percentages were calculated with respect to the sum of E + Z). Moreover, the formation of the E-isomer increased up to 20% after lowering the pH of the solution. Since the reverse reaction takes place when the pre-exposed solution is placed in dark, we followed the E to Z-isomer kinetics into the autosampler. The conversion rate was very slow when the autosampler was set at 4 °C (after 4 h the mean percentages of E-isomer were 50% for sunitinib and 22% for N-desethyl sunitinib). The reconversion rate was considerably accelerated with the increasing of the temperature: incubating the analytical solution in a heated water bath for 5 min at 70 °C we obtained the quantitative (99%) reconversion of the E- to the Z-isomer. No effect of concentration was observed, while the presence of acids inhibited the reconversion. Based on these results, a simple and fast procedure was setup to quantitatively reconvert the E-isomer formed during sample collection and processing without light protection into its Z-form thus leading to a single peak to quantify. The application of this additional step allows to develop a LC-MS/MS method suitable to clinical practice, due to its practicality and speed.


Assuntos
Indóis/sangue , Isomerismo , Luz/efeitos adversos , Pirróis/sangue , Sunitinibe/sangue , Cromatografia Líquida , Humanos , Concentração de Íons de Hidrogênio , Espectrometria de Massas em Tandem , Temperatura Ambiente , Fatores de Tempo
11.
Artigo em Inglês | MEDLINE | ID: mdl-30008308

RESUMO

Sunitinib is an oral FDA/EMEA approved multi-targeted tyrosine kinase inhibitor. It possesses anti-angiogenic and antitumor activity against a variety of advanced solid tumors. However, its chemical core does not allow a potential linkage to tumor-homing elements that could eventually enhance its potency. Therefore, a novel linkable sunitinib derivative, designated SB1, was rationally designed and synthesized. The pharmaceutical profile of SB1 was explored both in vitro and in vivo. Mass spectrometry and NMR spectroscopy were utilized for characterization, while MTT assays and LC-MS/MS validated protocols were used to explore its antiproliferative effect and stability, respectively. Cytotoxicity evaluation in three glioma cells showed that SB1 preserved the antiproliferative effect of sunitinib. SB1 was stable in vitro after 24 h incubation in mouse plasma, while both agents exhibited bioequivalent pharmacokinetic characteristics after i.v. administration in Balb/c mice. To evaluate the levels of SB1 in mouse plasma, a novel analytical method was developed and validated in accordance to the US FDA and the EU EMA guidelines. We formulated a novel linkable sunitinib analog exhibiting similar antiproliferative and apoptotic properties with native sunitinib in glioma cell lines. Both SB1 and native sunitinib showed identical in vitro stability in mouse plasma and pharmacokinetics after i.v. administration in Balb/c mice.


Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Indóis/química , Pirróis/química , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/análise , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Estabilidade de Medicamentos , Humanos , Indóis/sangue , Indóis/farmacocinética , Indóis/farmacologia , Modelos Lineares , Camundongos , Camundongos Endogâmicos BALB C , Pirróis/sangue , Pirróis/farmacocinética , Pirróis/farmacologia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sunitinibe
12.
Clin Ther ; 40(8): 1347-1356, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30017171

RESUMO

PURPOSE: Imrecoxib is one type of cyclooxygenase-2 inhibitor with the capability of reducing the potential cardiovascular risk caused by other NSAIDs. Co-administration with other medications can affect the cytochrome P450 (CYP) 2C9 enzyme function; thus, imrecoxib metabolism can be affected. The purpose of this research was to evaluate the effects of fluconazole, which is known to inhibit CYP2C9, on imrecoxib's pharmacokinetic (PK) parameters. METHODS: In this single-center, single-arm, open-label, self-controlled study, 12 healthy Chinese male volunteers (mean [SD] age, 22.6 [2.43] years) received the following 2 treatments separated by a washout period of 8 days under a fasting state: (1) a single oral dose of imrecoxib 100 mg; and (2) fluconazole 200 mg/d over 6 days followed by concurrent dosing of imrecoxib 100 mg and fluconazole 200 mg. Plasma concentrations of imrecoxib (M0) and its metabolites (4'-hydroxymethyl metabolite [M1] and 4'-carboxylic acid metabolite [M2]) for PK analysis were obtained at 0 (baseline) and 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, and 72 hours after imrecoxib dosing. Safety and tolerability assessments were performed throughout the study. FINDINGS: All subjects completed the study. There was 1 adverse event; drug-induced liver damage in 1 subject occurred after he received imrecoxib plus fluconazole, and the subject recovered without any sequelae. Coadministration with fluconazole resulted in much higher plasma imrecoxib concentrations, with an increase of 88% in Cmax and 72% in AUC0-t compared with only imrecoxib treatment, which showed that fluconazole may increase plasma exposure to imrecoxib. Fluconazole also caused a small, but not clinically relevant, decrease in M1 and M2 mean Cmax (13% and 14%, respectively), but there was minimal change in M1 and M2 mean AUC0-t (3% and 2%). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or adverse events between treatments. IMPLICATIONS: Concurrent administration of imrecoxib and fluconazole did not seem to change imrecoxib's safety profile. The ratio (imrecoxib + fluconazole/imrecoxib) for AUC0-t was 1.72 (90% CI, 1.41-2.11) and for Cmax it was 1.88 (90% CI, 1.59-2.21). Hence, it is necessary to adjust the imrecoxib dose when it is concurrently used with other CYP2C9 inhibitors.


Assuntos
Antifúngicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Fluconazol/farmacologia , Pirróis/farmacocinética , Sulfetos/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , China , Estudos Cross-Over , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/sangue , Interações de Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Pirróis/efeitos adversos , Pirróis/sangue , Distribuição Aleatória , Sulfetos/efeitos adversos , Sulfetos/sangue , Adulto Jovem
13.
Bioanalysis ; 10(11): 791-801, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29863414

RESUMO

AIM: To establish and validate an ultra-high-performance liquid chromatography-tandem mass spectrometry method for the rapid and simultaneous determination of famitinib and its metabolites in human plasma. RESULTS: All analytes demonstrated good correlation coefficients (R2 > 0.99), and the LLOQ was 0.05 ng/ml. The inter- and intraday accuracy and precision, as well as the stability of the samples, met the requirements of the US FDA. The extraction recovery and the matrix effect ranged from 87.58 to 116.06% and from 84.57 to 120.53%, respectively. CONCLUSION: The assay was successfully validated and applied to gastroenteropancreatic neuroendocrine tumor patients, and the assay may be used as a valuable tool in the clinic to determine the drug concentration of famitinib in the plasma of solid tumor patients.


Assuntos
Análise Química do Sangue/métodos , Cromatografia Líquida/métodos , Indóis/sangue , Indóis/metabolismo , Pirróis/sangue , Pirróis/metabolismo , Espectrometria de Massas em Tandem/métodos , Calibragem , Estudos de Viabilidade , Humanos , Limite de Detecção , Reprodutibilidade dos Testes , Fatores de Tempo
14.
Bioanalysis ; 10(11): 863-875, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29863892

RESUMO

AIM: Hemay005 is a novel small-molecule inhibitor of phosphodiesterase-4 developed for the treatment of psoriasis. Measurement of Hemay005 in biological samples is critical for evaluation of its pharmacokinetics in clinical studies. Methodology & results: Plasma and urine samples were extracted and then chromatographed on an Acquity UPLC HSS T3 column with a gradient elution. Detection was performed on a Xevo TQ-S tandem mass spectrometer using negative ESI. CONCLUSION: For the first time, a sensitive and robust ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was established and validated for the quantitative determination of Hemay005 in human plasma and urine, and it was successfully applied to evaluate the pharmacokinetics of Hemay005 in healthy subjects in a first-in-human study.


Assuntos
Acetamidas/sangue , Acetamidas/urina , Análise Química do Sangue/métodos , Cromatografia Líquida de Alta Pressão/métodos , Pirróis/sangue , Pirróis/urina , Espectrometria de Massas em Tandem/métodos , Tiofenos/sangue , Tiofenos/urina , Urinálise/métodos , Acetamidas/farmacocinética , Métodos Analíticos de Preparação de Amostras , Humanos , Inibidores da Fosfodiesterase 4/sangue , Inibidores da Fosfodiesterase 4/farmacocinética , Inibidores da Fosfodiesterase 4/urina , Pirróis/farmacocinética , Reprodutibilidade dos Testes , Tiofenos/farmacocinética
15.
Clin Pharmacol Drug Dev ; 7(6): 587-596, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29856518

RESUMO

Tofacitinib is an oral Janus kinase (JAK) inhibitor. This study characterized the pharmacokinetics of tofacitinib in patients with psoriasis and evaluated the impact of patient factors on disposition. Pooled phase 2/3 data (2981 patients: 9735 concentrations, dose range: 2-15 mg twice daily) up to 56 weeks were used for modeling. A one-compartment model parameterized in terms of apparent oral clearance (CL/F), apparent volume of distribution, zero-order absorption (duration, D), with interindividual variability and inter-occasion variability terms, described tofacitinib pharmacokinetics. A full covariate model incorporated effects for age, sex, race, ethnicity, and baseline variables (body weight, Psoriasis Area Severity Index [PASI], C-reactive protein [CRP], creatinine clearance [CrCl]). The parameter estimates (95%CI) for CL/F, Vd/F, and D in a typical individual (white, male, 86 kg, 46 years, CrCl 121 mL/min, PASI 19.8, and CRP 0.267 mg/dL) were 26.7 (25.9, 27.5) L/h, 125 (120.8, 128.3) liters, and 0.69 (0.646, 0.735) hours, respectively. Only CrCl led to clinically relevant changes in exposure. The analysis suggested no dosing modifications for age, body weight, sex, race, ethnicity, baseline PASI, or CRP based on the magnitude of exposure change. Dosing adjustments for renal impairment were derived from a separate phase 1 study.


Assuntos
Inibidores de Janus Quinases/sangue , Modelos Biológicos , Piperidinas/sangue , Psoríase/tratamento farmacológico , Pirimidinas/sangue , Pirróis/sangue , Adulto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Feminino , Humanos , Inativação Metabólica , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/uso terapêutico , Masculino , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Psoríase/metabolismo , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Índice de Gravidade de Doença , Distribuição Tecidual
16.
Int J Clin Oncol ; 23(5): 936-943, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29860539

RESUMO

BACKGROUND: The aim was to investigate the relationships between total sunitinib plasma concentrations (sunitinib plus its active metabolite; N-desethyl sunitinib) and clinical outcomes in Japanese patients with metastatic renal cell carcinoma (mRCC). METHODS: Twenty patients with mRCC were enrolled following treatment with sunitinib. To assess safety, the total sunitinib concentration range up to discontinuation of treatment and dosage reduction associated with adverse events within 6 weeks from initiating administration were analyzed. The longest administered sunitinib dosage was defined as the maintenance dose, and the relationship between total sunitinib concentration at the maintenance dosage and sunitinib efficacy was investigated. RESULTS: Total sunitinib concentration was significantly higher in patients who discontinued treatment or had dosage reduction due to adverse events within 6 weeks after initiation of sunitinib than in patients who continued treatment with the initial dosage. The time to treatment failure, progression-free survival, and overall survival were better in patients with total sunitinib concentrations < 50 ng/mL than in those with concentrations ≥ 50 ng/mL. CONCLUSIONS: The present study demonstrated that the effective range of total sunitinib concentration in Japanese patients with mRCC was lower than 50-100 ng/mL which was previously reported. These results indicate that therapeutic drug monitoring could maintain the therapeutic effect of sunitinib while minimizing adverse events by personalizing sunitinib dosages for Japanese patients with mRCC.


Assuntos
Antineoplásicos/sangue , Carcinoma de Células Renais/mortalidade , Indóis/sangue , Neoplasias Renais/mortalidade , Pirróis/sangue , Idoso , Antineoplásicos/administração & dosagem , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Indóis/administração & dosagem , Japão , Neoplasias Renais/sangue , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pirróis/administração & dosagem , Sunitinibe , Taxa de Sobrevida , Falha de Tratamento
17.
J Appl Toxicol ; 38(9): 1244-1250, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29766525

RESUMO

Compounds and products in the biocide and plant protection sector can only be registered after formal risk assessment to ensure safety for users and the environment. In bird and mammal risk assessment, this is routinely done using generic focal species as models, which are of particular exposure risk. Such a species is the common vole (Microtus arvalis) due to its high food intake relative to the low body weight. For wild species, biological samples, data and hence realistic exposure estimations are particularly difficult to obtain. In recent years, advances have been made in the techniques related to serial microsampling of laboratory mice and rats that allow for a reduction in sampling volumes. Similar progress in wild species sampling is missing. This study presents a proof of concept to dose wild rodents with relevant compounds and to draw serial, low volume blood samples suitable for state-of-the art toxicokinetic analyses. For the first time, the jugular vein of common voles was used to administer compounds (two frequently used fungicidal components). This procedure and the following microsampling of blood (2 × 10 µl six times within 24 hours) from the lateral tail vein did not affect body weight and mortality of voles. Samples were sufficient to detect dissipation patterns of the compounds from blood in toxicokinetic analysis. These results suggest that microsampling can be well translated from laboratory mice to wild rodent species and help to obtain realistic exposure estimates in wild rodents for ecotoxicological studies as well as to promote the 3R concept in studies with wild rodent species.


Assuntos
Arvicolinae/sangue , Coleta de Amostras Sanguíneas/métodos , Dioxóis/toxicidade , Ecotoxicologia/métodos , Exposição Ambiental/efeitos adversos , Monitoramento Ambiental/métodos , Fungicidas Industriais/toxicidade , Pirimidinas/toxicidade , Pirróis/toxicidade , Administração Intravenosa , Animais , Dioxóis/administração & dosagem , Dioxóis/sangue , Dioxóis/farmacocinética , Feminino , Fungicidas Industriais/administração & dosagem , Fungicidas Industriais/sangue , Fungicidas Industriais/farmacocinética , Masculino , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Pirimidinas/farmacocinética , Pirróis/administração & dosagem , Pirróis/sangue , Pirróis/farmacocinética , Reprodutibilidade dos Testes , Medição de Risco , Toxicocinética
18.
Eur J Drug Metab Pharmacokinet ; 43(4): 453-460, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29470718

RESUMO

BACKGROUND AND OBJECTIVES: Ulixertinib (BVD-523) is a novel and selective reversible inhibitor of ERK1/ERK2. The primary objectives of the study were to evaluate the pharmacokinetics of ulixertinib in mice, rats, and dogs followed by prediction of human pharmacokinetic profile by allometric equations with/without correction factors. METHODS: Oral and intravenous pharmacokinetic profiles of ulixertinib were generated in mice, rats, and dogs. The human intravenous pharmacokinetics profiles [volume of distribution (Vss) and clearance (CL)] were predicted employing simple allometry and using correction factors [maximum life span potential (MLP) and brain weight (BW)]. Pharmacokinetic data obtained from dogs were used to simulate human oral profile [area under the curve (AUC) and maximum plasma concentrations (Cmax)]. RESULTS: Post-intravenous administration the CL was moderate in dogs (15.5 mL/min/kg) and low in mice (6.24 mL/min/kg) and rats (1.67 mL/min/kg). Vss was 0.56, 0.36, and 1.61 L/kg in mice, rats, and dogs, respectively. The half-life (t½) of ulixertinib ranged between 1.0 and 2.5 h across the animal species. Following oral administration ulixertinib attained maximum concentration in plasma (Tmax) within 0.50-0.75 h in mice and rats, indicating that absorption was rapid; however, in dogs, Tmax attained at 2 h. Absolute oral bioavailability in mice and rats was > 92%; however, in dogs, it was 34%. By different allometric approaches, simple method and brain weight correction factor shown clear improvement in the prediction efficiency of allometric scaling for Vss (1.34-1.70 L/kg) and CL (4.18-6.09 mL/min/kg), respectively, comparing with the MLP method and simple method for CL. Similarly, simulation of oral human profile was attained from scaled values and dog data to predict reported human profile (AUC and Cmax). CONCLUSIONS: The derived pharmacokinetic parameters (AUC and Cmax at 600 mg dose) and simulated plasma concentration-time profiles of ulixertinib in humans were predicted with good confidence by allometric approach.


Assuntos
Aminopiridinas/farmacocinética , Pirróis/farmacocinética , Administração Intravenosa , Administração Oral , Aminopiridinas/administração & dosagem , Aminopiridinas/sangue , Animais , Disponibilidade Biológica , Simulação por Computador , Cães , Humanos , Masculino , Camundongos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Pirróis/administração & dosagem , Pirróis/sangue , Ratos , Especificidade da Espécie
19.
Br J Clin Pharmacol ; 84(6): 1136-1145, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29377257

RESUMO

AIMS: Tofacitinib is an oral, small molecule JAK inhibitor being investigated for ulcerative colitis (UC). In a phase 2 dose-ranging study, tofacitinib demonstrated efficacy vs. placebo as UC induction therapy. In this posthoc analysis, we aimed to compare tofacitinib dose and plasma concentration as predictors of efficacy and identify covariates that determined efficacy in patients with UC. METHODS: One- and two-compartment pharmacokinetic models, with first-order absorption and elimination, were evaluated to describe plasma tofacitinib concentration-time data at baseline and week 8. Relationships between tofacitinib exposure (dose, average plasma drug concentration during a dosing interval at steady state [Cav,ss ] and trough plasma concentration at steady state [Ctrough,ss ]) and week 8 efficacy endpoints were characterized using logistic regression analysis. Baseline disease, demographics, prior and concurrent UC treatment were evaluated as covariates. RESULTS: Plasma tofacitinib concentrations increased proportionately with dose and estimated oral clearance, and Cav,ss values were not significantly different between baseline and week 8. Dose, Cav,ss and Ctrough,ss performed similarly as predictors of efficacy based on statistical criteria for model fit and comparison of model predictions for each endpoint. Individual Cav,ss values were similar between clinical remitters and nonremitters at predicted efficacious doses (10 and 15 mg twice daily). Baseline Mayo score was a significant determinant of efficacy. Predicted differences from placebo in clinical remission at 10 mg twice daily for patients with baseline Mayo score >8 and ≤8 were 39% (95% CI: 7-70) and 21% (-2-50), respectively. CONCLUSIONS: Exposure-response characterization demonstrated the potential of tofacitinib 10 and 15 mg twice daily as induction therapy for UC without monitoring of plasma drug concentrations for dose optimization.


Assuntos
Anti-Inflamatórios/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/administração & dosagem , Inibidores de Janus Quinases/administração & dosagem , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Adulto , Idoso , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/sangue , Anti-Inflamatórios/farmacocinética , Colite Ulcerativa/sangue , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/imunologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/sangue , Fármacos Gastrointestinais/farmacocinética , Humanos , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/sangue , Inibidores de Janus Quinases/farmacocinética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Piperidinas/efeitos adversos , Piperidinas/sangue , Piperidinas/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/sangue , Pirimidinas/farmacocinética , Pirróis/efeitos adversos , Pirróis/sangue , Pirróis/farmacocinética , Indução de Remissão , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
20.
J Clin Pharmacol ; 58(3): 294-303, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29136283

RESUMO

Merck & Co., Inc. (Kenilworth, New Jersey) has recently published an integrated strategy for implementation of dried blood spots (DBS) in late-stage trials for population pharmacokinetic (PK) modeling. We applied this strategy for another late-stage clinical program: ubrogepant (MK-1602), a novel oral calcitonin gene-related peptide receptor antagonist for acute treatment of migraine. At the time of implementation, ubrogepant was entering phase 2 development. DBS was implemented to acquire PK information proximal to an acute migraine event to enable exposure-response modeling. The clinical endpoint was a spontaneous event, which generally occurs outside a clinic visit. Thus, an innovative feature of this trial was facilitating DBS in an outpatient setting. In vitro and bioanalytical tests established initial method feasibility and suitability for further evaluations in the clinic. A quantitative relationship was developed between blood and plasma concentrations from concurrently collected samples in a phase 1 (healthy subjects) and phase 2 (target patient population) study using graphical and population PK approaches. This integrated information was presented to the Food and Drug Administration for regulatory input. Following regulatory concurrence, DBS was poised for use in further clinical studies. Population PK modeling was used to dissect sources of variability contributing to DBS collection in the outpatient setting. What has been learned from this program has informed the broader integrated strategy of Merck & Co., Inc. (Kenilworth, NJ) for DBS implementation in clinical trials and research to improve the precision of PK data collected in an outpatient setting.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/sangue , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacocinética , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/tratamento farmacológico , Piridinas/sangue , Piridinas/farmacocinética , Pirróis/sangue , Pirróis/farmacocinética , Adulto , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Relação Dose-Resposta a Droga , Teste em Amostras de Sangue Seco , Feminino , Humanos , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Pirróis/administração & dosagem , Inquéritos e Questionários
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA