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1.
Pak J Pharm Sci ; 32(3): 1019-1024, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31278715

RESUMO

To compare the pharmacokinetics of candesartan cilexetil in healthy male and female volunteers in order to identify possible influence of gender and to improve therapeutic outcomes, an HPLC method for the quantification of candesartan cilexetil was developed and validated. Total of 16 volunteers (8 male and 8 female) were registered. Candesartan cilexetil 16 mg was administered orally to all the volunteers and blood samples were collected at different time intervals between 0-72 hours. Plasma was separated and analysed by HPLC method. Pharmacokinetic parameters were calculated by using APO software MW/PHARM version 3.02 and compared in male and female volunteers. The developed HPLC method fulfils the criteria for linearity, accuracy and precision described in EMA guideline. The values for absorption rate constant (Ka), maximum plasma concentration (Cmax), volume of distribution (Vd) and Clearance (CL) were similar in male and female volunteers. No influence of gender was observed on overall pharmacokinetics of candesartan cilexetil. Therefore, no need for dose optimization while administering candesartan cilexetil in male and female patients was found based on the results of this study.


Assuntos
Anti-Hipertensivos/sangue , Anti-Hipertensivos/farmacocinética , Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Compostos de Bifenilo/sangue , Compostos de Bifenilo/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Tetrazóis/sangue , Tetrazóis/farmacocinética , Adolescente , Adulto , Anti-Hipertensivos/administração & dosagem , Benzimidazóis/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Cromatografia de Fase Reversa/métodos , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Fatores Sexuais , Tetrazóis/administração & dosagem , Adulto Jovem
2.
J Pharmacol Exp Ther ; 370(2): 278-287, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31167814

RESUMO

Glecaprevir and pibrentasvir are oral direct-acting antiviral agents approved in combination for treatment of chronic hepatitis C viral infection. In vitro studies identified the combination as potentially clinically relevant inhibitors of the efflux transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Glecaprevir inhibited P-gp, BCRP, OATP1B1, and OATP1B3 with IC50 values of 0.33, 2.3, 0.017, and 0.064 µM, respectively. Pibrentasvir inhibited P-gp, BCRP, and OATP1B1 with IC50 values of 0.036, 14, and 1.3 µM, respectively. Neither agent inhibited organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, multidrug and toxin extrusion (MATE) 1, or MATE2K. Open-label phase 1 clinical drug-drug interaction studies were conducted in healthy subjects to evaluate interaction potential of glecaprevir/pibrentasvir and coadministered selective substrates for P-gp (digoxin, dabigatran etexilate, and sofosbuvir), BCRP (rosuvastatin and sofosbuvir), and OATP1B1/3 (pravastatin and rosuvastatin). The pharmacokinetic maximum plasma concentration (C max) and area under the concentration-time curve (AUC) parameters were evaluated for probe substrates alone and in combination with glecaprevir/pibrentasvir. The C max central values increased by 72%, 105%, 123%, 462%, and 66% for digoxin, dabigatran, pravastatin, rosuvastatin, and sofosbuvir, respectively, and the AUC central values increased by 48%, 138%, 130%, 115%, and 125% for digoxin, dabigatran, pravastatin, rosuvastatin, and sofosbuvir, respectively. Exposure of sofosbuvir metabolite GS-331007 (nucleoside analog) was similar with or without glecaprevir/pibrentasvir. The outcomes of the clinical drug-drug interaction studies confirmed clinically relevant inhibition of P-gp, BCRP, and OATP1B1/3, and were used to provide dosing guidance for the concomitant use of glecaprevir/pibrentasvir with relevant transporter substrates.


Assuntos
Benzimidazóis/farmacologia , Pirrolidinas/farmacologia , Quinoxalinas/farmacologia , Sulfonamidas/farmacologia , Pesquisa Médica Translacional , Adulto , Idoso , Benzimidazóis/farmacocinética , Transporte Biológico/efeitos dos fármacos , Combinação de Medicamentos , Interações de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Pessoa de Meia-Idade , Pirrolidinas/farmacocinética , Quinoxalinas/farmacocinética , Sulfonamidas/farmacocinética , Distribuição Tecidual , Adulto Jovem
3.
Exp Parasitol ; 204: 107718, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31201779

RESUMO

The aim of the current work was to evaluate a potential pharmacokinetic interaction between the flukicide triclabendazole (TCBZ) and the broad-spectrum benzimidazole (BZD) anthelmintic oxfendazole (OFZ) in sheep. To this end, both an in vitro assay in microsomal fractions and an in vivo trial in lambs parasitized with Haemonchus contortus resistant to OFZ and its reduced derivative fenbendazole (FBZ) were carried out. Sheep microsomal fractions were incubated together with OFZ, FBZ, TCBZ, or a combination of either FBZ and TCBZ or OFZ and TCBZ. OFZ production was significantly diminished upon coincubation of FBZ and TCBZ, whereas neither FBZ nor OFZ affected the S-oxidation of TCBZ towards its sulfoxide and sulfone metabolites. For the in vivo trial, lambs were treated with OFZ (Vermox® oral drench at a single dose of 5 mg/kg PO), TCBZ (Fasinex® oral drench at a single dose of 12 mg/kg PO) or both compounds at a single dose of 5 (Vermox®) and 12 mg/kg (Fasinex®) PO. Blood samples were taken to quantify drug and metabolite concentrations, and pharmacokinetic parameters were calculated by means of non-compartmental analysis. Results showed that the pharmacokinetic parameters of active molecules and metabolites were not significantly altered upon coadministration. The sole exception was the increase in the mean residence time (MRT) of OFZ and FBZ sulfone upon coadministration, with no significant changes in the remaining pharmacokinetic parameters. This research is a further contribution to the study of metabolic drug-drug interactions that may affect anthelmintic efficacies in ruminants.


Assuntos
Anti-Helmínticos/farmacocinética , Benzimidazóis/farmacocinética , Triclabendazol/farmacocinética , Animais , Anti-Helmínticos/metabolismo , Área Sob a Curva , Benzimidazóis/metabolismo , Biotransformação , Sistema Enzimático do Citocromo P-450/metabolismo , Interações de Medicamentos , Fenbendazol/metabolismo , Fígado/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Oxigenases/metabolismo , Ovinos , Triclabendazol/metabolismo
4.
Biomed Chromatogr ; 33(10): e4607, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31141832

RESUMO

A simple, precise and accurate HPLC method was developed, optimized and validated for simultaneous determination of rosuvastatin and candesartan in rat plasma using atorvastatin as an internal standard. Solid-phase extraction was used for sample cleanup and its subsequent optimization was carried out to achieve higher extraction efficiency and to eliminate matrix effect. A quality by design approach was used, wherein three-level factorial design was applied for optimization of mobile phase composition and for assessing the effect of pH of the mobile phase using Design Expert Software. Adequate separation for both analytes was achieved with a Waters C18 column (250 × 4.6 mm, 5 µm) using acetonitrile-5 mm sodium acetate buffer (70:30, v/v; pH adjusted to 3.5 with acetic acid) as a mobile phase at a flow rate of 1.0 mL/min and wavelength of 254 nm. The calibration curves were linear over the concentration ranges 5-150 and 10-300 ng/mL for rosuvastatin (ROS) and candesartan (CAN), respectively. The validated method was successfully applied to a pharmacokinetic study in Wistar rats and the data did not reveal any evidence for a potential drug-drug interaction between ROS and CAN. This information provides evidence for clinical rational use of ROS and CAN.


Assuntos
Benzimidazóis/sangue , Cromatografia Líquida de Alta Pressão/métodos , Rosuvastatina Cálcica/sangue , Tetrazóis/sangue , Animais , Benzimidazóis/química , Benzimidazóis/farmacocinética , Modelos Lineares , Masculino , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/farmacocinética , Sensibilidade e Especificidade , Extração em Fase Sólida , Tetrazóis/química , Tetrazóis/farmacocinética
5.
Biomed Chromatogr ; 33(8): e4545, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30937940

RESUMO

A novel rapid and highly sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) bioanalytical method was established for the analysis of flibanserin in human plasma. Flibanserin d4 was used as internal standard (IS). Flibanserin and the internal standard (IS) were extracted from the plasma using protein precipitation technique with acetonitrile. A Kinetex C18 (2.6 µm, 2.1 × 50 mm) column was used for chromatographic separation and the mobile phase was a mixture of 20 mm ammonium acetate buffer (pH 4.5)-acetonitrile (50:50, v/v) with an isocratic elution mode and a flow rate of 0.3 mL/min. The analysis was performed on a Xefo TQD Waters mass spectrometer in multiple reaction monitoring mode with a positive electrospray ionization interface. The US Food and Drug Administration guidelines were followed during the bio-analytical methods validation regarding linearity, precision, accuracy, carryover, selectivity, dilution integrity and stability. The analysis run time was carried out within 2 min over a wide linear concentration range of 5-1000 ng mL-1 . Finally, the proposed method was successfully used in a pharmacokinetic study that measured flibanserin concentration in healthy, non-pregnant female volunteers after a single 100 mg oral dose of flibanserin.


Assuntos
Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Benzimidazóis/química , Estabilidade de Medicamentos , Feminino , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes
6.
Oncology ; 96(4): 217-222, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30844808

RESUMO

OBJECTIVES: Tissue factor overexpression is associated with tumor progression, venous thromboembolism, and worsened survival in patients with cancer. Tissue factor and activated factor VII (FVIIa) complex may contribute to tumor invasiveness by promoting cell migration and angiogenesis. The study objective was to evaluate safety, pharmacokinetics, and efficacy of PCI-27483, a selective FVIIa inhibitor. METHODS: This was an open-label, multicenter phase 2 trial of patients with advanced pancreatic cancer. Part A of the study was an intrapatient dose escalation lead-in portion in patients concurrently receiving gemcitabine, and in part B, patients were randomized 1: 1 to the recommended phase 2 dose combination PCI-27483-gemcitabine versus gemcitabine alone. RESULTS: Target international normalized ratio (between 2.0-3.0) was achieved following PCI-27483 treatment. Overall safety of PCI-27483-gemcitabine (n = 26) was similar to gemcitabine alone (n = 16), with a higher incidence of mostly low-grade bleeding events (65% vs. 19%). Progression-free survival (PFS) and overall survival (OS) were not significantly different between patients treated with PCI-27483-gemcitabine (PFS: 3.7 months, OS: 5.7 months) and those treated with gemcitabine alone (PFS: 1.9 months, OS: 5.6 months). CONCLUSIONS: Targeted inhibition of the coagulation cascade was achieved by administering PCI-27483. PCI-27483-gemcitabine was well tolerated, but superiority to single agent gemcitabine was not demonstrated.


Assuntos
Anticoagulantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácido Aspártico/análogos & derivados , Benzimidazóis/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fator VIIa/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácido Aspártico/administração & dosagem , Ácido Aspártico/efeitos adversos , Ácido Aspártico/farmacocinética , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/secundário , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Monitoramento de Medicamentos/métodos , Fator VIIa/metabolismo , Feminino , Hemorragia/induzido quimicamente , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Intervalo Livre de Progressão , Fatores de Tempo
7.
Leuk Res ; 79: 38-44, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30849661

RESUMO

Glasdegib is a potent and selective oral inhibitor of the Hedgehog pathway. We report data from the single-arm, lead-in cohort of an open-label phase 1b/2 trial of glasdegib in patients with primary/secondary myelofibrosis (MF) previously treated with at least one Janus kinase inhibitor (JAKi). Patients received glasdegib 100 mg orally once daily until there was no further clinical benefit. Primary endpoints included adverse events (AEs). Secondary endpoints included patients with spleen volume reduction (SVR) ≥35% at week 24, patients with ≥50% total symptom score (TSS) reduction, and pharmacokinetics. All 21 treated patients had one or more AE and five (23.8%) had serious AEs. Most common (>30%) AEs were dysgeusia (61.9%), muscle spasms (57.1%), alopecia (38.1%), fatigue (33.3%), and decreased appetite (33.3%). Although no patient had ≥35% SVR at week 24, one patient previously treated with ruxolitinib had an SVR of 32.9%. At week 12, two (9.5%) patients had ≥50% reduction in TSS from baseline and ˜40% had ≥20% reduction. One patient had an anaemia response. Following administration of glasdegib 100 mg once daily, the median time to peak plasma concentrations at steady-state generally occurred at 1 h post-dose. The safety profile of glasdegib monotherapy was manageable in patients with primary/secondary MF. Further study of glasdegib in combination with JAKi in a MF population may be warranted.


Assuntos
Benzimidazóis/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Pirazóis/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/farmacocinética , Quimioterapia Adjuvante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos dos fármacos , Compostos de Fenilureia/farmacocinética , Mielofibrose Primária/metabolismo , Mielofibrose Primária/mortalidade , Mielofibrose Primária/patologia , Baço/efeitos dos fármacos , Baço/patologia , Resultado do Tratamento , Adulto Jovem
8.
Exp Parasitol ; 199: 52-58, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30831078

RESUMO

Ascaris suum is a widespread parasitic nematode that causes infection in pigs with high prevalence rates. Oxfendazole (OFZ) is effective against A. suum when used at a single high oral dose of 30 mg/kg. The aim of this study was to assess the pattern of distribution/accumulation of OFZ and its metabolites, in bloodstream (plasma), mucosal tissue and contents from small and large intestine and adult specimens of A. suum collected from infected and treated pigs. The activity of glutathione-S-transferases (GSTs) in A. suum was also investigated. Infected pigs were orally treated with OFZ (30 mg/kg) and sacrificed at 0, 3, 6 and 12 h after treatment. Samples of blood, mucosa and contents from both small and large intestine as well as adult worms were obtained and processed for quantification of OFZ/metabolites by HPLC. OFZ was the main analyte measured in all of the evaluated matrixes. The highest drug concentrations were determined in small (AUC0-t 718.7 ±â€¯283.5 µg h/g) and large (399.6 ±â€¯110.5 µg h/g) intestinal content. Concentrations ranging from 1.35 to 2.60 µg/g (OFZ) were measured in adult A. suum. GSTs activity was higher after exposure to OFZ both in vivo and ex vivo. The data obtained here suggest that the pattern of OFZ accumulation in A. suum would be more related to the concentration achieved in the fluid and mucosa of the small intestine than in other tissues/fluids. It is expected that increments in the amount of drug attained in the tissues/fluids of parasite location will correlate with increased drug concentration within the target parasite, and therefore with the resultant treatment efficacy. The results are particularly relevant considering the potential of OFZ to be used for soil transmitted helminths (STH) control programs and the advantages of pigs as a model to assess drug treatment to be implemented in humans.


Assuntos
Antinematódeos/farmacocinética , Ascaríase/tratamento farmacológico , Ascaris suum/metabolismo , Benzimidazóis/farmacocinética , Animais , Antinematódeos/uso terapêutico , Área Sob a Curva , Ascaríase/metabolismo , Ascaríase/parasitologia , Benzimidazóis/uso terapêutico , Cromatografia Líquida de Alta Pressão , Citosol/enzimologia , Dinitroclorobenzeno/metabolismo , Fezes/parasitologia , Feminino , Fenbendazol/análise , Glutationa Transferase/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/parasitologia , Intestino Grosso/metabolismo , Intestino Delgado/metabolismo , Contagem de Ovos de Parasitas , Espectrofotometria , Suínos
9.
Int J Toxicol ; 38(2): 96-109, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30791754

RESUMO

BT-11 is an orally active, gut-restricted investigational therapeutic targeting the lanthionine synthetase C-like 2 pathway with lead indications in ulcerative colitis (UC) and Crohn disease (CD), 2 manifestations of inflammatory bowel disease (IBD). In 5 mouse models of IBD, BT-11 is effective at oral doses of 8 mg/kg. BT-11 was also efficacious at nanomolar concentrations in primary human samples from patients with UC and CD. BT-11 was tested under Good Laboratory Practice conditions in 90-day repeat-dose general toxicity studies in rats and dogs, toxicokinetics, respiratory, cardiovascular and central nervous system safety pharmacology, and genotoxicity studies. Oral BT-11 did not cause any clinical signs of toxicity, biochemical or hematological changes, or macroscopic or microscopic changes to organs in 90-day repeat-dose toxicity studies in rats and dogs at doses up to 1,000 mg/kg/d. Oral BT-11 resulted in low systemic exposure in both rats (area under the curve exposure from t = 0 to t = 8 hours [AUC0-8] of 216 h × ng/mL) and dogs (650 h × ng/mL) and rapid clearance with an average half-life of 3 hours. BT-11 did not induce changes in respiratory function, electrocardiogram parameters, or behavior with single oral doses of 1,000 mg/kg/d. There was no evidence of mutagenic or genotoxic potential for BT-11 up to tested limit doses using an Ames test, chromosomal aberration assay in human peripheral blood lymphocytes, or micronucleus assay in rats. Therefore, nonclinical studies show BT-11 to be a safe and well-tolerated oral therapeutic with potential as a potent immunometabolic therapy for UC and CD with no-observed adverse effect level >1,000 mg/kg in in vivo studies.


Assuntos
Benzimidazóis/farmacocinética , Benzimidazóis/toxicidade , Proteínas de Membrana/antagonistas & inibidores , Piperazinas/farmacocinética , Piperazinas/toxicidade , Administração Oral , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Masculino , Ratos Wistar , Testes de Toxicidade
10.
Oncogene ; 38(20): 3886-3902, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30692638

RESUMO

Palbociclib is a selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) approved for the treatment of some cancers. The main mechanism of action of palbociclib is to induce cell cycle arrest and senescence on responsive cells. Here, we report that palbociclib concentrates in intracellular acidic vesicles, where it can be readily observed due to its intrinsic fluorescence, and it is released from these vesicles upon dilution or washing out of the extracellular medium. This reversible storage of drugs into acidic vesicles is generally known as lysosomal trapping and, based on this, we uncover novel properties of palbociclib. In particular, a short exposure of cells to palbociclib is sufficient to produce a stable cell-cycle arrest and long-term senescence. Moreover, after washing out the drug, palbociclib-treated cells release the drug to the medium and this conditioned medium is active on susceptible cells. Interestingly, cancer cells resistant to palbociclib also accumulate and release the drug producing paracrine senescence on susceptible cells. Finally, other lysosomotropic drugs, such as chloroquine, interfere with the accumulation of palbociclib into lysosomes, thereby reducing the minimal dose of palbociclib required for cell-cycle arrest and senescence. In summary, lysosomal trapping explains the prolonged temporal activity of palbociclib, the paracrine activity of exposed cells, and the cooperation with lysosomotropic drugs. These are important features that may help to improve the therapeutic dosing and efficacy of palbociclib. Finally, two other clinically approved CDK4/6 inhibitors, ribociclib and abemaciclib, present a similar behavior as palbociclib, suggesting that lysosomal trapping is a property common to all three clinically-approved CDK4/6 inhibitors.


Assuntos
Antineoplásicos/farmacocinética , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Piperazinas/farmacocinética , Piridinas/farmacocinética , Laranja Acridina/química , Aminopiridinas/farmacocinética , Benzimidazóis/farmacocinética , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Citocinas/metabolismo , Corantes Fluorescentes/química , Humanos , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Purinas/farmacocinética
11.
Am J Cardiovasc Drugs ; 19(3): 335-342, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30637626

RESUMO

INTRODUCTION AND OBJECTIVE: Pulmonary capillary endothelial transient receptor potential vanilloid 4 (TRPV4) channel plays a critical role in mediating the development of cardiogenic pulmonary edema. GSK2798745 is a first-in-class, highly potent, selective, orally active TRPV4 channel blocker being evaluated in a first-time-in-humans study (NCT02119260). METHODS: GSK2798745 was administered in a randomized, placebo-controlled study design to healthy volunteers in three separate cohorts as single escalating doses, with and without food, and as once-daily repeat doses for up to 14 days, respectively. Two cohorts of subjects with mild to moderate heart failure were also administered GSK2798745 once daily for up to 7 days. Safety, tolerability, and systemic exposure data were collected. RESULTS: No significant safety issues or serious adverse events were observed with GSK2798745 in healthy volunteers and patients with heart failure. GSK2798745 systemic exposure data demonstrated linear pharmacokinetics up to 12.5 mg, less than twofold accumulation with once-daily dosing, and a systemic half-life of ~ 13 h. There was a slight increase in GSK2798745 exposure [14% increase in area under the plasma concentration-time curve (AUC) and 9% increase in maximum observed plasma concentration (Cmax)] after administration with a high-fat meal. CONCLUSIONS: GSK2798745 was well-tolerated in healthy volunteers and patients with stable heart failure. The safety and exposure data obtained in this study allow further evaluation of the drug in long-term clinical studies in heart failure as well as other indications.


Assuntos
Benzimidazóis , Interações Alimento-Droga , Insuficiência Cardíaca/tratamento farmacológico , Compostos de Espiro , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Área Sob a Curva , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Benzimidazóis/uso terapêutico , Estudos de Casos e Controles , Método Duplo-Cego , Esquema de Medicação , Feminino , Meia-Vida , Humanos , Masculino , Compostos de Espiro/efeitos adversos , Compostos de Espiro/farmacocinética , Compostos de Espiro/uso terapêutico
12.
J Pharm Biomed Anal ; 166: 20-29, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30599278

RESUMO

Lifirafenib (BGB-283), a dual inhibitor trageting BRAF kinase and EGFR, showed favorable efficacy and safety in treating patients with different cancer types harboring mutations in BRAF, KRAS and NRAS. In order to support the clinical pharmacokinetic study, a sensitive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated to quantify lifirafenib concentration in human plasma and urine. Plasma samples were purified using protein precipitation. Urine samples were pre-treated by adding tween 80 with the purpose of preventing non-specific adsorption, then extracted by centrifugation. Chromatographic separation was achieved on Phenomenex Luna C18 column with a gradient elution. The mass detection was performed using electrospray ionization (ESI) source under multiple reaction monitoring (MRM) in positive ionization mode. The method was fully validated, and the result of inter-assay and intra-assay precisions were less than 15% and the accuracy within the scope of ±15%. The linear range for plasma and urine covered from 10 to 10,000 ng/mL and 1 to 200 ng/mL, respectively, with correlation coefficients of 0.99. The validation for matrix effect, recovery, stability and carryover were met the acceptance criteria. The method showed robust and sensitive, it successfully fulfilled the requirement of clinical pharmacokinetic study of lifirafenib in Chinese patients with locally advanced or metastatic solid tumors.


Assuntos
Benzimidazóis/análise , Cromatografia Líquida de Alta Pressão/métodos , Naftiridinas/análise , Espectrometria de Massas em Tandem/métodos , Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Benzimidazóis/urina , Confiabilidade dos Dados , Humanos , Naftiridinas/sangue , Naftiridinas/farmacocinética , Naftiridinas/urina , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray
13.
Expert Rev Anti Infect Ther ; 17(1): 51-56, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30501436

RESUMO

INTRODUCTION: Oxfendazole (methyl [5-(phenylsulphinyl)-1H benzimidazole-2-yl] carbamate) has a particularly long metabolic half-life in ruminants, and its metabolite fenbendazole also has anthelminthic action. A very limited number of drugs are available for the treatment of some zoonotic helminth infections, such as neurocysticercosis and echinococcosis. More recent work has expanded oxfendazole's nonclinical safety profile and demonstrated its safety and bioavailability in healthy human volunteers, thus advancing the possibility of a new and greatly needed option for antiparasitic treatment of geohelminths and tissue parasites. Areas covered: The present article reviews evidence supporting the safety and efficacy of oxfendazole against both gut and tissue dwelling helminths in animals, as well as more recent safety and pharmacokinetic data supporting its potential for use in human parasitoses. Expert commentary: The pharmacokinetics, safety, and wide spectrum of efficacy of oxfendazole are consistently demonstrated in intestinal helminth infections of animals as well as in tissue dwelling larval cestode and trematode infections in diverse animal species. Now supported by first-in-human safety and pharmacokinetic data, oxfendazole becomes a promising alternative to the limited portfolio of antiparasitic drugs available to treat helminthic diseases of humans.


Assuntos
Anti-Helmínticos/uso terapêutico , Benzimidazóis/uso terapêutico , Helmintíase/tratamento farmacológico , Animais , Anti-Helmínticos/efeitos adversos , Anti-Helmínticos/farmacocinética , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Disponibilidade Biológica , Meia-Vida , Helmintíase/parasitologia , Helmintíase Animal/tratamento farmacológico , Helmintíase Animal/parasitologia , Humanos , Zoonoses/tratamento farmacológico , Zoonoses/parasitologia
14.
Cancer Chemother Pharmacol ; 83(2): 319-328, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30456480

RESUMO

PURPOSE: Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in older patients with relapsed or refractory acute myeloid leukemia (AML) or AML arising from pre-existing myeloid malignancies. We aimed to perform quantitative assessments of pharmacokinetics, efficacy, and safety of veliparib in this patient population to inform future trial design. METHODS: Population pharmacokinetic analysis was performed using Phoenix® NLME with pharmacokinetic data obtained from 37 subjects after oral administration of veliparib in a Phase I study with and without temozolomide. Effect of covariates (age, sex, BMI, creatinine clearance (CLCR), and co-administration of temozolomide) on the pharmacokinetics of veliparib were evaluated, as well as impact of veliparib exposure on mucositis (dose-limiting toxicity), objective response rate (ORR), and overall survival. RESULTS: A two-compartment model with first-order elimination and a first-order absorption with lag-time adequately described veliparib pharmacokinetics. CLCR and body weight were clinically significant covariates for veliparib disposition. The proportion of subjects with all grade mucositis increased with veliparib exposure (AUC). However, no trend in ORR and overall survival was observed with increasing exposure. CONCLUSIONS: Veliparib with temozolomide presents a promising combination for older patients with myeloid leukemias. An exposure-safety relationship was established for this combination. Further clinical investigations aimed at elucidating the veliparib exposure-efficacy/safety relationship and optimizing dosing recommendations for maximizing benefit-risk in patients with advanced myeloid malignancies should study veliparib doses ranging up to 120 mg in combination with temozolomide.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Leucemia Mieloide Aguda/tratamento farmacológico , Mucosite/epidemiologia , Temozolomida/administração & dosagem , Temozolomida/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/farmacocinética , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Incidência , Leucemia Mieloide Aguda/patologia , Masculino , Maryland/epidemiologia , Pessoa de Meia-Idade , Modelos Estatísticos , Mucosite/induzido quimicamente , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Prognóstico , Distribuição Tecidual , Adulto Jovem
15.
Expert Opin Drug Metab Toxicol ; 15(2): 85-91, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30577708

RESUMO

INTRODUCTION: The combination of cyclin-dependent kinases 4 and 6 (CDK 4 and 6) inhibitors with endocrine therapy represents a new standard of care for endocrine-receptor positive metastatic breast cancer. Currently, three compounds are approved. Abemaciclib is the latest CDK4/6 inhibitor approved by the US Food and Drug Administration in view of the results of the MONARCH1 and 2 trials. Area covered: In this article, we review the preclinical and clinical development of abemaciclib in advanced breast cancer, describing current therapeutic indications and open questions. Expert opinion: Results of phase III trials investigating abemaciclib in patients with endocrine-receptor positive metastatic breast cancer have shown a substantial improvement in progression-free-survival, with a safe and manageable toxicity profile. In order to better select patients who will more likely respond to CDK4/6 inhibitors, biomarkers need to be identified. To optimize CDK4/6 targeting, combination therapies are being tested in several ongoing trials.


Assuntos
Aminopiridinas/administração & dosagem , Benzimidazóis/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Intervalo Livre de Doença , Feminino , Humanos , Metástase Neoplásica , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia
16.
Xenobiotica ; 49(5): 584-590, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-29790816

RESUMO

The pharmacokinetics of TAK-272 (SCO-272), an orally active renin inhibitor, was investigated in rats with subcutaneously injected turpentine oil, which was an inflammation animal model. Following intravenous administration of TAK-272 to the turpentine-treated rats, the systemic clearance and volume of distribution decreased with the elevated plasma α1-acid glycoprotein (AGP) levels. The elevated plasma AGP levels were negatively correlated with the plasma unbound fraction of TAK-272 in the rats. Although the AUCs of total TAK-272 in the turpentine-treated rats were higher than those in the control rats after intravenous and oral administration, those of unbound TAK-272, which seem to directly contribute to the pharmacological effect and safety, were nearly equal between the turpentine-treated and control rats in the respective dose routes. TAK-272 has been shown to primarily bind to AGP in the human plasma. These results strongly suggested that the pharmacokinetic of TAK-272 in humans would also be affected by the variation in the plasma AGP levels and should be discussed with not only the total concentrations but also the unbound concentrations in the clinical trial for patients with elevated plasma AGP levels.


Assuntos
Benzimidazóis/farmacologia , Benzimidazóis/farmacocinética , Morfolinas/farmacologia , Morfolinas/farmacocinética , Orosomucoide/metabolismo , Piperidinas/farmacologia , Piperidinas/farmacocinética , Renina/antagonistas & inibidores , Administração Oral , Animais , Benzimidazóis/efeitos adversos , Masculino , Morfolinas/efeitos adversos , Piperidinas/efeitos adversos , Ratos , Ratos Sprague-Dawley , Terebintina/farmacocinética , Terebintina/farmacologia
17.
Eur J Pharm Sci ; 128: 180-192, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30468868

RESUMO

Bilastine is a non-sedating second-generation H1 antihistamine approved for treatment of allergic rhinoconjunctivitis (AR) and urticaria (U) in adults at the oral (p.o.) dose of 20 mg once daily (OD). Optimal attributes can be anticipated for its clinical use in pediatrics due to its favorable safety and tolerability and age-independent PD profile. The aim of this work was to characterize bilastine PK in children through population modeling of data from a limited sampling confirmatory clinical trial in children with AR or U. The objective was also to ascertain whether the proposed dose (10 mg/day) in the target pediatric subset aged 2-<12 years matches the systemic exposure seen in adults at the 20 mg/day dose. A popPK model characterizing bilastine PK behavior in children aged from 4 to <12 years treated with 10 mg oral bilastine daily was successfully developed and qualified. No relationship was found between bilastine PK and age or weight; stopping rules pre-stablished to finalize the trial, i.e., model completeness and no dependence of exposure on decreasing age, were thus fulfilled. On a second step, the popPK model in children was linked to the PD model in adults assuming the same PD as described in adults and used to compare the PD outcome between both populations. Finally, an allometric scaling method and a physiological approximation were used to evaluate the suitability of the selected dose in the youngest children, showing that children from 2 years were deemed to belong to the same population as well. The achievement of comparable PK (i.e., within the range) to that observed in adults after the therapeutic dose of 20 mg, together with the achievement of similar PD and additional integrative analysis, served to confirm the validity of the 10 mg daily dose for the target pediatric subset (2 to <12 years).


Assuntos
Benzimidazóis/farmacocinética , Benzimidazóis/uso terapêutico , Antagonistas dos Receptores Histamínicos H1 não Sedativos/farmacocinética , Antagonistas dos Receptores Histamínicos H1 não Sedativos/uso terapêutico , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Área Sob a Curva , Benzimidazóis/administração & dosagem , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Antagonistas dos Receptores Histamínicos H1 não Sedativos/administração & dosagem , Humanos , Masculino , Modelos Biológicos , Piperidinas/administração & dosagem , Urticária/tratamento farmacológico
18.
Cancer Chemother Pharmacol ; 83(3): 463-472, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30536154

RESUMO

PURPOSE: To demonstrate the bioequivalence of the planned maleate salt-based commercial glasdegib tablet formulation [International Council for Harmonization (ICH) glasdegib] to the clinical di-hydrochloride (di-HCl) salt-based glasdegib formulation (di-HCl glasdegib). Additionally, to estimate the effects of a high-fat, high-calorie meal and proton-pump inhibitor (PPI) on the pharmacokinetics of ICH glasdegib. METHODS: This Phase I open-label study (ClinicalTrials.gov: NCT03130556) enrolled 24 healthy subjects to receive two different tablet formulations of single-dose 100-mg glasdegib under fasted conditions. A subset of healthy volunteers (n = 12) received single-dose 100-mg ICH glasdegib following a high-fat, high-calorie meal or concurrently with a PPI (rabeprazole). RESULTS: The adjusted geometric mean ratio (ICH glasdegib:di-HCl glasdegib) and 90% confidence intervals (CI) of area under the plasma concentration-time curve from time zero to infinity (AUCinf) and maximum plasma concentration (Cmax) were 104.0% (99.7‒108.5%) and 101.6% (96.1‒107.4%), respectively, within the acceptance range for bioequivalence (80‒125%). The adjusted geometric mean ratio (90% CIs) for AUCinf and Cmax under fed conditions were 84.3% (78.6‒90.6%) and 69.0% (61.8‒77.0%), respectively, relative to fasted conditions. When ICH glasdegib was administered concurrently with the PPI, the adjusted geometric mean ratio (90% CI) of AUCinf and Cmax were 100.6% (93.2‒108.6%) and 80.5% (70.7‒91.6%), respectively, relative to fasted conditions. Glasdegib was generally well tolerated under all conditions studied. CONCLUSIONS: The ICH glasdegib tablet formulation was bioequivalent to the clinical di-HCl formulation under fasted conditions. A high-fat, high-calorie meal or concurrent PPI treatment had a minimal effect on glasdegib exposure, and was not considered clinically meaningful.


Assuntos
Benzimidazóis/farmacocinética , Dieta Hiperlipídica , Interações Alimento-Droga , Compostos de Fenilureia/farmacocinética , Inibidores da Bomba de Prótons/farmacocinética , Administração Oral , Adolescente , Adulto , Área Sob a Curva , Benzimidazóis/administração & dosagem , Interações de Medicamentos , Jejum , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Comprimidos , Equivalência Terapêutica , Adulto Jovem
19.
Bioorg Chem ; 83: 250-261, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30391698

RESUMO

A new series of benzimidazothiazole derivatives has been synthesized. The structure of the products was confirmed by spectroscopic techniques such as IR, NMR and mass spectroscopy. The tested compounds were evaluated for their anti-inflammatory activity either in vitro through the COX enzyme inhibition assay, or in vivo through carrageenan paw edema technique. Results revealed that compound 25 and 29 represented the most active ones among the entire series with % inhibition 72.19, 72.07 for COX-1, and 87.46, 87.38 for COX-2, respectively. Interestingly, all synthesized compounds exhibited IC50 values less than both reference drugs celecoxib and naproxen, indicating their superior potency. For compound 25, it showed about 340 and 198 times more potent than celecoxib and naproxen respectively as COX-1 inhibitor (IC50 value 0.044 vs. 15.000 and 8.700 µM), and 10 and 115 times more potent than the same drugs as COX-2 inhibitor (IC50 value 4.52 vs. 40.00 and 520.00 nM). The antitumor activity of the products was also evaluated and the results obtained are consistent with those obtained by the anti-inflammatory screening where compounds 25 and 29 proved to be the most active ones among the other compounds with %GI ranging from 31.5 to 62.5% and they exhibited the lowest IC50 values as well. The ADMET analysis of the tested compounds was also performed in addition to the molecular modeling studies that included flexible alignment, surface and electrostatic maps in addition to the Lipinisk's rule of five.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Tiazóis/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Domínio Catalítico , Linhagem Celular Tumoral , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Drogas , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinética
20.
Eur J Clin Pharmacol ; 75(2): 217-226, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30341499

RESUMO

PURPOSE: This study characterized the effects of hepatic impairment on the pharmacokinetics and safety of glecaprevir and pibrentasvir, two direct-acting antivirals used for treatment of chronic HCV infection. METHODS: HCV-negative subjects with normal hepatic function, or with mild (Child-Pugh [CP]-A), moderate (CP-B), or severe (CP-C) hepatic impairment received single doses of pibrentasvir 120 mg alone or with glecaprevir 200 mg or 300 mg (n = 6/functional group/dose). Plasma pharmacokinetics and protein binding were evaluated. Doses were separated by ≥ 14 days of washout. RESULTS: For the approved combination of glecaprevir 300 mg with pibrentasvir 120 mg, glecaprevir AUC was increased by 33% (CP-A), to 2.0-fold (CP-B), and to 11-fold (CP-C) relative to normal subjects; pibrentasvir AUC was ≤ 26% different (CP-A or CP-B) and increased to 2.1-fold (CP-C). For glecaprevir 200 mg with pibrentasvir 120 mg, glecaprevir AUC was increased by 80% (CP-A) or to 2.8-fold (CP-B), while pibrentasvir AUC was unaffected in the same subjects (≤ 12% difference). Pibrentasvir 120 mg alone AUC increased 51% (CP-A), 31% (CP-B), and to 5.2-fold (CP-C). The unbound fraction of glecaprevir was higher in CP-C subjects than normal subjects and pibrentasvir protein binding was similar across groups. The most common adverse event was headache; no events were serious. CONCLUSION: This study supported evaluation of the glecaprevir 300 mg with pibrentasvir 120-mg combination in HCV-infected subjects with CP-A hepatic impairment without dose adjustment. Elevated glecaprevir and/or pibrentasvir exposures are expected in HCV-infected patients with CP-B or CP-C hepatic impairment.


Assuntos
Antivirais/efeitos adversos , Antivirais/farmacocinética , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Hepatopatias/dietoterapia , Quinoxalinas/efeitos adversos , Quinoxalinas/farmacocinética , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Adolescente , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Hepatopatias/metabolismo , Masculino , Pessoa de Meia-Idade , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico
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