Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 18 de 18
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-31082683

RESUMO

Thiazolidinediones and quinazolin-4-ones compounds, previously known for their activity against Type 2 diabetes and antifungal activity respectively, are currently being investigated for their anti-cancer activity. The determination of pharmacokinetic parameters for these two classes of compounds using a simultaneous chromatographic method with a low detection limit is a challenge. In this study, a highly sensitive and simultaneous LC-MS/MS-based bioanalytical method was developed and validated in rat plasma for the estimation of four novel anti-cancer compounds, BIT-15-67 and BNT-11, belonging to the Thiazolidinedione class, and BNUA-108 and BNUA-48, from the quinazolin-4-one class. The analytes were extracted from plasma samples by protein precipitation and separated on a short reverse phase Hypersil Phenyl BDS, 50 × 4.6 mm, 2.4 µm column at a column oven temperature of 40 °C. An isocratic mobile phase, a 20:80 (v/v) mixture of 5 mM ammonium acetate solution and acetonitrile containing 0.1% formic acid, was used for the elution at a flow rate of 0.4 mL/min. The analytes and internal standard, sulfaphenazole, were quantified in the multiple reaction monitoring mode using positive electrospray ionization with specific pair of mass by charge ratio. All standard validation parameters were assessed as per current bioanalytical method validation guidelines in rat plasma. The area response for the four analytes was found to be linear over the concentration range of 1.00 to 1000 ng/mL in rat plasma. The signal to noise at LLOQ of 1 ng/mL was adequate for application to different pre-clinical studies. The intra- and inter-day precision were <11% and accuracy deviated -1.8 to 9.60% from the nominal. The mean recovery was high (about 90%) and consistent for all the analytes over the linear dynamic range of the method. This simple, robust and validated method can be employed to determine the rat plasma concentrations of the four selected anticancer compounds in preclinical studies such as the pharmacodynamic and the pharmacokinetic studies including tissue distribution and excretion, and the toxicokinetic studies. In this study, pharmacokinetic parameters were determined using this method for all the four compounds individually following intravenous administration in rats.


Assuntos
Antineoplásicos/sangue , Cromatografia Líquida/métodos , Quinazolinonas/sangue , Espectrometria de Massas em Tandem/métodos , Tiazolidinedionas/sangue , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Tiazolidinedionas/química , Tiazolidinedionas/farmacocinética
2.
Biomed Chromatogr ; 33(5): e4511, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30773664

RESUMO

The purpose of this study was to develop and validate an LC-MS/MS method for simultaneous determination of idelalisib and GS-563117 in dog plasma. The analytes were extracted using ethyl acetate and then separated on a Waters Acquity UPLC BEH C18 column (50 × 2.1 mm, i. d., 1.7 µm) using 0.1% formic acid in water and acetonitrile as mobile phase at a flow rate of 0.3 mL/min in gradient elution mode. The analytes were quantified using selected reaction monitoring with precursor-to-product transitions at m/z 416.2 → 176.1, m/z 432.2 → 192.1 and m/z 421.2 → 176.1 for idelalisib, GS-563117 and [2 H5 ]-idelalisib (internal standard). The assay showed good linearity (r > 0.9992) over the tested concentration range of 0.1-600 ng/mL for idelalisib and 0.1-300 ng/mL for GS-563117. The intra- and inter-day RSD values for idelalisib and GS-563117 were <8.84 and 12.41%, respectively. The intra- and inter-day RE values were within the range of -7.21-8.52%, and -6.44-14.23%, respectively. The extraction recovery was found to be >84.59% and no matrix effects were observed. The validated LC-MS/MS method has been successfully applied for the simultaneous determination of idelalisib and GS-563117 in a pharmacokinetic study in dogs. Our results suggested that idelalisib was rapidly metabolized into its metabolite GS-563117 in dog and the in vivo exposure of GS-563117 was 17.59% of that of idelalisib.


Assuntos
Cromatografia Líquida/métodos , Purinas/sangue , Purinas/metabolismo , Quinazolinonas/sangue , Quinazolinonas/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Cães , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Masculino , Purinas/química , Purinas/farmacocinética , Quinazolinonas/química , Quinazolinonas/farmacocinética , Reprodutibilidade dos Testes
3.
J Pharm Biomed Anal ; 166: 66-70, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30612075

RESUMO

Dacomitinib is a highly selective irreversible small-molecule inhibitor of the human epidermal growth factor receptor (HER) family of tyrosine kinases. A simple and quick bioanalytical method was completely developed and validated for the assay and pharmacokinetic investigation of dacomitinib in rat plasma using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Proteins in 0.1 mL plasma samples were prepared by precipitant acetonitrile containing ibrutinib as the internal standard (IS). Separation of the analyte from plasma samples was carried out on an Acquity UPLC BEH C18 column using acetonitrile and 0.1% formic acid in water as mobile phase for gradient elution. The total run time and the elution time of dacomitinib were 3.0 min and 1.07 min, respectively. Positive-ion electrospray ionization (ESI) and multiple reaction monitoring (MRM) on a triple quadrupole tandem mass spectrometer were used for detection at the transitions of m/z 470.1 → 124.1 for dacomitinib and m/z 441.2 → 84.3 for ibrutinib (IS), respectively. In the range of 1-150 ng/mL, the calibration curve of dacomitinib was linear with a lower limit of quantitation (LLOQ) of 1 ng/mL. Mean recovery of dacomitinib in plasma was in the range of 76.9-84.1%. The inter- and intra-day precision (RSD) was in the scope of 1.7-8.7% and the accuracy (RE) ranged from -6.1 to 8.5%. Stability studies under different conditions were indicated to be stable. A pharmacokinetic study after oral administration of 40 mg/kg dacomitinib in rats illustrated the applicability of the new presented determination of dacomitinib.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Quinazolinonas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Confiabilidade dos Dados , Limite de Detecção , Masculino , Pirazóis/sangue , Pirazóis/farmacocinética , Pirimidinas/sangue , Pirimidinas/farmacocinética , Quinazolinonas/sangue , Ratos , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray
4.
J Med Chem ; 62(2): 688-698, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30516998

RESUMO

Phosphodiesterase 10A (PDE10A) is a newly identified therapeutic target for central-nervous-system disorders. 2-(2-(3-(4-([18F]Fluoroethoxy)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]MNI-659, [18F]5) is a useful positron-emission-tomography (PET) ligand for imaging of PDE10A in the human brain. However, the radiolabeled metabolite of [18F]5 can accumulate in the brain. In this study, using [18F]5 as a lead compound, we designed four new 18F-labeled ligands ([18F]6-9) to find one more suitable than [18F]5. Of these, 2-(2-(3-(4-([18F]fluoromethoxy- d2)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]9) exhibited high in vitro binding affinity ( Ki = 2.9 nM) to PDE10A and suitable lipophilicity (log D = 2.2). In PET studies, the binding potential (BPND) of [18F]9 (5.8) to PDE10A in the striatum of rat brains was significantly higher than that of [18F]5 (4.6). Furthermore, metabolite analysis showed much lower levels of contamination with radiolabeled metabolites in the brains of rats given [18F]9 than in those given [18F]5. In conclusion, [18F]9 is a useful PET ligand for PDE10A imaging in brain.


Assuntos
Diester Fosfórico Hidrolases/metabolismo , Ftalimidas/química , Quinazolinonas/química , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Avaliação Pré-Clínica de Medicamentos , Radioisótopos de Flúor/química , Marcação por Isótopo , Ligantes , Masculino , Camundongos , Diester Fosfórico Hidrolases/química , Ftalimidas/sangue , Ftalimidas/metabolismo , Tomografia por Emissão de Pósitrons , Ligação Proteica , Quinazolinonas/sangue , Quinazolinonas/metabolismo , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
5.
Ther Drug Monit ; 40(2): 237-244, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29529009

RESUMO

BACKGROUND: Idelalisib is the first orally active selective phosphatidylinositol 3-kinase delta inhibitor approved by Food and Drug Administration and European Medicines Agency in 2014 for the treatment of several types of blood cancer. Idelalisib is widely used as a monotherapy or in combination with rituximab, bendamustine, or ofatumumab with a significant efficacy. However, idelalisib has shown increased risk of infection and a higher frequency of serious adverse events. It may be useful to determine idelalisib concentration in human plasma to adjust dose and to manage adverse effects in clinical practice. METHODS: After a single-step protein precipitation of plasma samples, the chromatographic separation was performed using an ultra-high performance liquid chromatography system coupled with mass tandem spectrometry in a negative ionization mode using isotope-labeled internal standard. This method was validated by studies of its linearity, accuracy, imprecision, limit of quantification, recovery, matrix effect, selectivity, and stability. RESULTS: The quantification method was linear from 10 to 2500 ng/mL with a 5 ng/mL lower limit of quantification that encompasses the clinical range of drug concentration. The intraday and interday imprecisions were below 8.1% and 11.4%, respectively. The recoveries and matrix effect of idelalisib were 85.6% ± 1.2% and 95.7% ± 3.0%, respectively, which are consistent, precise, and reproducible (coefficient of variation % < 15%). Peak plasma concentration and trough plasma concentration ranges of idelalisib reached 1591-1937 ng/mL and 256.3-303.3 ng/mL, respectively, in 3 follicular lymphoma patients treated with idelalisib 150 mg twice a day. CONCLUSIONS: A robust and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated to quantify idelalisib concentration in human plasma. This method was effectively applied to 3 follicular lymphoma patients.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas/métodos , Purinas/sangue , Quinazolinonas/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Estudos de Avaliação como Assunto , Humanos , Reprodutibilidade dos Testes
6.
Xenobiotica ; 48(5): 459-466, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28648122

RESUMO

1. This study aimed to characterise the pharmacokinetics of dacomitinib, a pan-human epidermal growth factor receptor tyrosine kinase inhibitor, and its metabolite, PF-05199265, in healthy Chinese subjects. 2. In this open-label, single-centre, nonrandomised study (NCT02097433), 14 subjects received a single dacomitinib 45-mg oral dose. Pharmacokinetic samples for dacomitinib and PF-05199265 were collected pre- and postdose. Subjects were genotyped for cytochrome P450 (CYP)2D6 metaboliser status. Safety was assessed throughout the study. 3. The geometric mean (per cent coefficient of variability) area under the concentration-time curve from time zero to infinity (AUCinf) and maximum plasma concentration (Cmax) were 1662 ngch/mL (26%) and 21.51 ng/mL (27%), respectively, for dacomitinib and 469 ngch/mL (65%) and 5.54 ng/mL (79%) for PF-05199265. Median times to Cmax were 8 and 4 h postdose for dacomitinib and PF-05199265, respectively; mean terminal half-life of dacomitinib was 62.7 h. Geometric mean apparent clearance and volume of distribution of dacomitinib were 27.06 L/h and 2415 L, respectively. The metabolite PF-05199265-to-dacomitinib ratios were 0.2907 for AUCinf and 0.2656 for Cmax. 4. Dacomitinib total (AUCinf) and peak exposures (Cmax) were similar among subjects with different CYP2D6 genotypes, whereas both parameters for PF-05199265 were higher in extensive metabolisers (n = 5) versus intermediate metabolisers (n = 8).


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Citocromo P-450 CYP2D6/genética , Quinazolinonas/farmacocinética , Adulto , Alelos , Área Sob a Curva , Feminino , Humanos , Masculino , Farmacogenética , Quinazolinonas/efeitos adversos , Quinazolinonas/sangue
7.
Lung Cancer ; 106: 76-82, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28285698

RESUMO

OBJECTIVES: Dacomitinib is a pan-HER inhibitor for advanced non-small-cell lung cancer (NSCLC). We explored the impact of a planned 4-day dacomitinib dose interruption on plasma exposure of dacomitinib and adverse events (AEs) of interest in Cohort III of the ARCHER 1042 study. MATERIALS AND METHODS: Patients, treatment-naïve for advanced NSCLC with EGFR activating mutations, received oral dacomitinib 45mg QD (once daily). A planned dose interruption occurred in Cycle 1 from Days 11 through 14. The primary endpoint was the pharmacokinetic (PK) characteristics of dacomitinib in Cycle 1Day 10 and during dose interruption. Secondary endpoints included safety and concomitant medications used to treat AEs of interest. RESULTS: Cohort III enrolled 25 patients. Median plasma Cmax of dacomitinib in Cycle 1 Day 10 was 83.40ng/mL. Average median plasma dacomitinib concentration during the 4-day dose interruption was 42.63ng/mL. In the first 8 weeks of treatment 1) 80% of patients used concomitant medications for dermatologic AEs, 76% for diarrhea, and 44% for stomatitis, and 2) all patients experienced treatment-emergent AEs and 28% had all-causality Grade 3 AEs. CONCLUSION: At 45mg QD dosing, PK parameters of plasma dacomitinib in Cycle 1 Day 10 were comparable to that obtained in Cycle 1 Day 14 from other dacomitinib studies. Average median plasma dacomitinib concentration during the 4-day dose interruption was approximately half of the median plasma Cmax of dacomitinib observed prior to dose interruption. The toxicity profile was consistent with that from other studies of dacomitinib.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Relação Dose-Resposta a Droga , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinonas/sangue , Estudos de Coortes , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Quinazolinas/uso terapêutico , Quinazolinonas/administração & dosagem , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacocinética , República da Coreia , Resultado do Tratamento
8.
Neuropharmacology ; 117: 171-181, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28122201

RESUMO

Phosphodiesterase 10A (PDE10A) is an enzyme highly enriched in the striatal medium spiny neurons. It is involved in the regulation of cytoplasmic levels of cAMP and cGMP and signaling within the basal ganglia. This study with PDE10A radioligand [18F]MNI-659 was designed to measure the enzyme occupancy of PF-02545920 in 8 healthy male volunteers (48 ± 4 years) after a single oral dose (10 mg or 20 mg) and to evaluate safety and tolerability. Arterial blood sampling was performed to obtain a metabolite-corrected plasma input function for the quantification of [18F]MNI-659 binding to PDE10A. The occupancy of PF-02545920 was calculated with two different methods: In Method 1, [18F]MNI-659 enzyme occupancy was calculated from the estimates of binding potential, using the cerebellum as a reference region; in Method 2, occupancy was estimated from the slope of the revised Lassen's plot. Serum concentrations of PF-02545920 were measured to determine the relationship between concentration and occupancy. Based on Method 1, striatal PDE10A occupancy increased with increasing PF-02545920 dose: 14-27% at 10 mg dose (N = 4) and 45-63% at 20 mg dose (N = 3). Comparable occupancies were observed using Lassen's plot Method 2: 10 mg: 14-37%; 20 mg: 46-55%. The relationship between exposure and occupancy was best described using an Emax model. The serum concentration associated with 50% occupancy was estimated to be 93.2 ng/mL. Single oral doses of 10 mg or 20 mg of PF-02545920 were safe and well tolerated in healthy male volunteers [NCT# 01918202].


Assuntos
Diester Fosfórico Hidrolases/metabolismo , Pirazóis/farmacologia , Quinolinas/farmacologia , Adulto , Corpo Estriado/metabolismo , Radioisótopos de Flúor/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Ftalimidas/sangue , Ftalimidas/metabolismo , Tomografia por Emissão de Pósitrons , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Quinazolinonas/sangue , Quinazolinonas/metabolismo , Quinolinas/efeitos adversos , Quinolinas/farmacocinética , Ensaio Radioligante/métodos
9.
Invest New Drugs ; 33(4): 931-41, 2015 08.
Artigo em Inglês | MEDLINE | ID: mdl-26048096

RESUMO

Dacomitinib (PF-00299804) is a small-molecule inhibitor of the tyrosine kinases human epidermal growth factor receptor-1 (HER1; epidermal growth factor receptor, EGFR), HER2, and HER4 currently being developed for the treatment of lung cancer with sensitizing mutations in EGFR or refractory to EGFR-directed treatment. Dacomitinib is largely metabolized by the liver through oxidative and conjugative metabolism; therefore, determination of the impact of varying degrees of hepatic impairment on the pharmacokinetics (PK) of dacomitinib was warranted to ensure patient safety. In this phase I, open-label, parallel-group study, a single dose of dacomitinib was administered to healthy volunteers and to subjects with mild or moderate liver dysfunction, as determined by Child-Pugh classification. The primary goal of this study was to evaluate the effects of mild and moderate hepatic impairment on the single-dose PK profile of dacomitinib, as well as to assess the safety and tolerability in these subjects. Plasma protein binding and impact of hepatic function on the PK of the active metabolite PF-05199265 was also investigated. Twenty-five male subjects received dacomitinib 30 mg, with 8 subjects in the healthy- and mild-impairment cohorts and 9 subjects in the moderate-impairment cohort. Compared with healthy volunteers, there was no significant change in dacomitinib exposure in subjects with mild or moderate liver dysfunction and no observed alteration in plasma protein binding. No serious treatment-related adverse events were reported in any group, and dacomitinib was well tolerated. A dose adjustment does not appear necessary when administering dacomitinib to patients with mild or moderate hepatic impairment.


Assuntos
Antineoplásicos/farmacocinética , Hepatopatias/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinonas/farmacocinética , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Proteínas Sanguíneas/metabolismo , Citocromo P-450 CYP2D6/genética , Receptores ErbB/antagonistas & inibidores , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Quinazolinonas/efeitos adversos , Quinazolinonas/sangue
10.
J Chromatogr Sci ; 53(9): 1542-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25935158

RESUMO

A rapid, sensitive and simple high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of the antileishmanial agent, S010-0269, in hamster serum. A Discovery HS C-18 column (5 µm, 50 × 4.6 mm) maintained at 40°C was utilized for chromatographic separation with mobile phase [acetonitrile: aqueous ammonium acetate (0.01 M) buffer (85:15, v/v)] at a flow rate of 0.6 mL/min. The method requires low serum volume (20 µL) with a run time of 3.5 min. Excellent linear relationships (r ≥ 0.99) were obtained between the measured and added concentration over a range of 1-200 ng/mL. Validation parameters (accuracy, specificity, precision, recovery, matrix effect and stability) were assessed as per FDA guidelines. The precision and accuracy were acceptable as indicated by relative standard deviation ranging from 2.3 to 13.6% and bias values ranging from 1.5 to 6.5%, respectively. Moreover, the compound was found stable in hamster serum even after 30 days of storage at -80°C and being subjected to two freeze-thaw cycles. The validated method was successfully applied to the pharmacokinetic study after 10 mg/kg oral dose of S010-0269 in hamsters.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Quinazolinonas/sangue , Espectrometria de Massas em Tandem/métodos , Tripanossomicidas/sangue , Animais , Cricetinae , Limite de Detecção , Modelos Lineares , Masculino , Mesocricetus , Quinazolinonas/química , Quinazolinonas/farmacocinética , Reprodutibilidade dos Testes , Tripanossomicidas/química , Tripanossomicidas/farmacocinética
11.
Invest New Drugs ; 33(4): 895-900, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25937431

RESUMO

BACKGROUND: Dacomitinib is an irreversible oral pan-HER tyrosine kinase inhibitor with antitumor activity demonstrated in patients with recurrent/metastatic (RM) SCCHN. A Phase I trial of dacomitinib with standard therapy in LA SCCHN is ongoing (NCT01737008). As enteral feeding is needed for many SCCHN patients, this study investigated the PK properties of dacomitinib when administered via GT (NCT01484847). Since patients with GT are difficult to recruit, this study also determined the feasibility of PK assessments using a unique design in LA SCCHN patients with GT, by giving a single dose of drug during their radiotherapy (co-administration with chemotherapy avoided). METHODS: Eligible patients were given a single dose of crushed dacomitinib at 45 mg in water suspension via GT. All doses were administered in fasting state and supine position. PK samples were drawn prior to dose (t = 0), 30 min and 1, 2, 3, 4, 6, 12, 24, 48, 72, 96, 144, 168, 192 and 216 hrs post-dose, and analyzed by HPLC-MS/MS. PK parameters (mean [CV%]) of this study were compared with those of dacomitinib given orally using Student t test. RESULTS: Six patients with LA SCCHN patients were enrolled. The median age of patients was 54 years. Two different types of GT were used: 14 F Cope-loop tube (n = 3), 20 F PEG/disc retention tube (n = 3). PK study showed t1/2 of 58 h, Cmax of 17 ng/ml, Tmax of 8 h, AUC0-inf of 1185 ng*hr/ml, Vd/F of 3310 L and CL/F of 41 L/hr. CONCLUSION: Compared with oral dosing of intact immediate release (IR) tablets, GT administration resulted in 34 % reduction in Cmax and 33-44 % decrease in AUC (all p <0.05) (Jänne et al., Clin Cancer Res 2011). Such differences were not detected when compared with the PK properties of dacomitinib administered orally in aqueous suspension (Bello et al., Cancer Chemother Pharm 2013). These differences may be attributed to aqueous suspension of dacomitinib. Caution should be taken with GT administration of orally active small molecule targeted therapy. This study also demonstrated that PK trials in GT patients are feasible using novel designs.


Assuntos
Antineoplásicos/farmacocinética , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinonas/farmacocinética , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Nutrição Enteral , Receptores ErbB/antagonistas & inibidores , Feminino , Gastrostomia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Quinazolinonas/administração & dosagem , Quinazolinonas/efeitos adversos , Quinazolinonas/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço
12.
J Clin Pharmacol ; 55(8): 909-19, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25760671

RESUMO

Idelalisib, a potent phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor, is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by cytochrome P450 (CYP) 3A and uridine 5'-diphospho-glucuronosyltransferase 1A4. In vitro, idelalisib inhibits P-glycoprotein (P-gp) and organic anion transporting polypeptides 1B1 and 1B3, and GS-563117 is a time-dependent CYP3A inhibitor. This study enrolled 24 healthy subjects and evaluated (1) the effect of idelalisib on the pharmacokinetics (PK) of digoxin, a P-gp probe substrate, rosuvastatin, a breast cancer resistance protein, and OATP1B1/OATP1B3 substrate, and midazolam, a CYP3A substrate; and (2) the effect of a strong inducer, rifampin, on idelalisib PK. On treatment, the most common clinical adverse events (AEs) were headache and pyrexia. Grade 3 transaminase increases were observed in 5 of 24 subjects and were reversible. Two subjects had serious AEs after treatment completion (grade 3 pyrexia and/or drug-induced liver injury). Idelalisib coadministration did not affect digoxin and rosuvastatin PK. Coadministration with idelalisib increased plasma exposures of midazolam (138% and 437% for maximum observed plasma concentration [Cmax ] and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUCinf ], respectively), consistent with the in vitro finding of CYP3A inhibition by GS-563117. Rifampin caused a substantial decrease in idelalisib (58% and 75%, Cmax and AUCinf , respectively) and GS-563117 exposures, indicating an enhanced contribution of CYP3A to idelalisib metabolism under a strongly induced state.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Purinas/farmacologia , Purinas/farmacocinética , Quinazolinonas/farmacologia , Quinazolinonas/farmacocinética , Adulto , Antineoplásicos/sangue , Digoxina/sangue , Digoxina/farmacocinética , Interações de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Midazolam/sangue , Midazolam/farmacocinética , Pessoa de Meia-Idade , Purinas/sangue , Quinazolinonas/sangue , Rifampina/farmacologia , Rosuvastatina Cálcica/sangue , Rosuvastatina Cálcica/farmacocinética , Adulto Jovem
13.
Artigo em Inglês | MEDLINE | ID: mdl-24463402

RESUMO

A sensitive and reliable high-performance liquid chromatography-mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous quantification of idelalisib, fludarabine and lenalidomide using tolbutamide as an internal standard. Analytes were recovered by liquid-liquid extraction and separated on a reverse phase C18 column (150mm×4.6mm i.d., 5µm) using methanol:0.1% formic acid buffer (70:30) as mobile phase at a flow rate of 1mL/min in isocratic mode. Selective reaction monitoring was performed using the transitions, i.e. m/z 416.25/176.48, 286.11/154.10, 260.15/149.15, and 271.14/155.06 to quantify idelalisib, fludarabine and lenalidomide and tolbutamide, respectively. The method was validated over the concentration range of 1.15-576.84ng/mL for idelalisib, 0.95-476.25ng/mL for fludarabine and 0.97-486.19ng/mL for lenalidomide. Intra and inter-day accuracy and precision of validated method were within the acceptable limits of <15%. Coefficients of correlation (r(2)) for the calibration curves were >0.998 for all analytes. The method was successfully applied for simultaneous estimation of idelalisib, fludarabine and lenalidomide in a pharmacokinetic study in rats.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Purinas/sangue , Quinazolinonas/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Talidomida/análogos & derivados , Vidarabina/análogos & derivados , Animais , Estabilidade de Medicamentos , Lenalidomida , Masculino , Purinas/química , Purinas/farmacocinética , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos , Talidomida/sangue , Talidomida/química , Talidomida/farmacocinética , Vidarabina/sangue , Vidarabina/química , Vidarabina/farmacocinética
14.
J Clin Pharmacol ; 54(5): 555-62, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24293056

RESUMO

Dacomitinib is currently in development for the treatment of non-small cell lung cancer. Formation of the major circulating metabolite (PF-05199265) is mediated by cytochrome P450 (CYP) 2D6 and CYP2C9. This phase I, single fixed-sequence, two-period study evaluated the effect of paroxetine, a CYP2D6 inactivator, on dacomitinib pharmacokinetics in healthy volunteers who were extensive CYP2D6 metabolizers. Subjects received a single 45-mg dacomitinib dose alone and in combination with paroxetine (30 mg/day for 10 consecutive days, with dacomitinib administered on day 4) at steady-state levels. Blood samples were collected through 240 hours post-dacomitinib dosing. Dacomitinib exposure (area under the concentration-time curve from 0 to infinity; AUCinf) increased 37%; however a reduction in PF-05199265 AUCinf of approximately 90% was observed during the paroxetine treatment period. The maximum concentration of dacomitinib changed minimally. Adverse events reported with single-dose dacomitinib administered alone or in the presence of steady-state levels of paroxetine were mostly mild, and no serious adverse events were reported. While paroxetine significantly inhibited CYP2D6-mediated metabolism of a single dose of dacomitinib, the modest effect on dacomitinib exposure is unlikely to be clinically relevant when dacomitinib is given daily. Dose adjustment of dacomitinib may therefore not be required upon coadministration with a CYP2D6 inhibitor.


Assuntos
Inibidores do Citocromo P-450 CYP2D6/farmacologia , Paroxetina/farmacologia , Quinazolinonas/farmacocinética , Adulto , Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP2D6/efeitos adversos , Inibidores do Citocromo P-450 CYP2D6/sangue , Inibidores do Citocromo P-450 CYP2D6/farmacocinética , Interações de Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Paroxetina/efeitos adversos , Paroxetina/sangue , Paroxetina/farmacocinética , Quinazolinonas/efeitos adversos , Quinazolinonas/sangue , Adulto Jovem
15.
Artigo em Inglês | MEDLINE | ID: mdl-23435343

RESUMO

Automated sample extraction for regulated bioanalysis by liquid chromatography/tandem mass spectrometry (LC-MS/MS) still presents significant challenges. A new sample preparation methodology with a simplified and completely automated workflow was developed to overcome these challenges using cap piercing for direct biofluid transfer and evaporation-free solid phase extraction (SPE). Using pierceable cap sample tubes, a robotic liquid handler was able to sample without uncapping or recapping during sample preparation. Evaporation for SPE was eliminated by using a mobile phase-compatible elution solvent followed by sample dilution prior to LC-MS/MS analysis. Presented here are three LC-MS/MS assays validated using this methodology to support three CNS drug development programs: (1) BMS-763534 and its metabolite, BMS-790318, in dog plasma; (2) BMS-694153 in monkey plasma; and (3) Pexacerfont (BMS-562086) and two metabolites, BMS-749241 and DPH-123554, in human plasma. These assays were linear from 1.00 to 1000 or 2.00 to 2000ng/mL for each analyte with excellent assay accuracy, precision and reproducibility. These assays met acceptance criteria for regulated bioanalysis and have been successfully applied to drug development study samples. The methodology described here successfully eliminated all manual intervention steps achieving fully automated sample preparation without compromising assay performance. Importantly, this methodology eliminates the potential exposure of the bioanalyst to any infectious biofluids during sample preparation.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Indazóis/sangue , Pirazóis/sangue , Quinazolinonas/sangue , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Extração em Fase Sólida/métodos , Manejo de Espécimes/métodos , Espectrometria de Massas em Tandem/métodos , Triazinas/sangue , Animais , Cromatografia Líquida/economia , Cromatografia Líquida/instrumentação , Cromatografia Líquida/métodos , Cães , Desenho de Equipamento , Haplorrinos , Ensaios de Triagem em Larga Escala/economia , Ensaios de Triagem em Larga Escala/instrumentação , Ensaios de Triagem em Larga Escala/métodos , Humanos , Indazóis/metabolismo , Pirazóis/metabolismo , Quinazolinonas/metabolismo , Sensibilidade e Especificidade , Extração em Fase Sólida/economia , Extração em Fase Sólida/instrumentação , Manejo de Espécimes/economia , Manejo de Espécimes/instrumentação , Espectrometria de Massas em Tandem/economia , Espectrometria de Massas em Tandem/instrumentação , Triazinas/metabolismo
16.
Invest New Drugs ; 30(6): 2352-63, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22249430

RESUMO

BACKGROUND: Dacomitinib (PF-00299804) is an oral, irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases. METHODS: This phase I, open-label, dose-escalation study (clinicaltrials.gov: NCT00783328) primarily evaluated the safety and tolerability of dacomitinib by dose-limiting toxicity (DLT), and determined the clinically recommended phase II dose (RP2D) in Japanese patients with advanced solid tumors. Dacomitinib was administered orally at three dose levels (15, 30, or 45 mg once daily [QD]). Patients initially received a single dose, and after 9 days of follow-up, continuously QD in 21-day cycles. Endpoints included pharmacokinetics (PK) and antitumor activity. RESULTS: Thirteen patients were assigned to the three dose levels (15 mg cohort: n = 3; 30 mg cohort: n = 3; 45 mg cohort: n = 7) according to a traditional '3 + 3' design. None of the treated patients experienced a DLT. Toxicities were manageable and similar in type to those observed in other studies. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Of 13 evaluable patients, one with NSCLC (adenocarcinoma) had a partial response and nine patients had stable disease. CONCLUSIONS: Dacomitinib 45 mg QD was defined as the RP2D and demonstrated preliminary activity in Japanese patients with advanced solid tumors.


Assuntos
Antineoplásicos/administração & dosagem , Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Quinazolinonas/administração & dosagem , Administração Oral , Adulto , Idoso , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Grupo com Ancestrais do Continente Asiático , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Esquema de Medicação , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Neoplasias/metabolismo , Neoplasias/patologia , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Quinazolinonas/sangue , Quinazolinonas/farmacocinética , Carga Tumoral/efeitos dos fármacos , Proteínas ras/genética
17.
J Endourol ; 25(1): 107-12, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21204688

RESUMO

BACKGROUND AND PURPOSE: Urethral strictures are from periurethral spongiofibrosis that develops as a result of urethral trauma, disease, or iatrogenic injury. The spongy tissue that surrounds the strictured urethra has an altered ratio of collagen, with increased collagen type I relative to type III. We evaluated the ability of a urethral catheter that was coated with halofuginone (HF), a potent type I collagen inhibitor, to prevent spongiofibrosis formation in a rat model. MATERIALS AND METHODS: HF was coated on silicone catheters and release kinetics were measured. Success of impregnation was evaluated with scanning electron microscopy, serial weights, and drug elution data. Urethral strictures were induced in rats using electrocautery. Half the animals had placement of an HF-coated catheter while the others had uncoated silicone controls. Animals were sacrificed at predetermined time points, and urethral tissue was either processed for staining with Masson trichrome and anti-alpha-1 collagen or digested to determine HF concentration. Serum drug levels were also determined in treated animals. Slides were graded by a pathologist who was blinded to treatment to determine collagen deposition. RESULTS: HF was coated successfully on silicone catheters. Local urethral concentration of HF was tenfold higher than serum concentration in treated rats. Animals with HF-coated catheters had no new type I collagen deposition after urethral injury. Control animals had increased periurethral collagen type I deposition, typical of urethral stricture formation. CONCLUSIONS: HF can be coated successfully on silicone catheters. HF successfully inhibits periurethral type I collagen deposition after urethral injury. This may become an important therapy to prevent urethral stricture formation or recurrence after endoscopic therapy.


Assuntos
Cateteres , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Uretra/efeitos dos fármacos , Doenças Uretrais/prevenção & controle , Animais , Cicatriz/patologia , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Masculino , Piperidinas/sangue , Quinazolinonas/sangue , Ratos , Ratos Sprague-Dawley , Coloração e Rotulagem , Stents , Uretra/patologia , Doenças Uretrais/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA