RESUMEN
Erdafitinib, a selective and potent oral pan-FGFR inhibitor, is metabolized mainly through CYP2C9 and CYP3A4 enzymes. This phase 1, open-label, single-sequence, drug-drug interaction study evaluated the pharmacokinetics, safety, and tolerability of a single oral dose of erdafitinib alone and when co-administered with steady state oral carbamazepine, a dual inducer of CYP3A4 and CYP2C9, in 13 healthy adult participants (NCT04330248). Compared with erdafitinib administration alone, carbamazepine co-administration decreased total and free maximum plasma concentrations of erdafitinib (Cmax) by 35% (95% CI 30%-39%) and 22% (95% CI 17%-27%), respectively. The areas under the concentration-time curve over the time interval from 0 to 168 hours, to the last quantifiable data point, and to time infinity (AUC168h, AUClast, AUCinf), were markedly decreased for both total erdafitinib (56%-62%) and free erdafitinib (48%-55%). The safety profile of erdafitinib was consistent with previous clinical studies in healthy participants, with no new safety concerns when administered with or without carbamazepine. Co-administration with carbamazepine may reduce the activity of erdafitinib due to reduced exposure. Concomitant use of strong CYP3A4 inducers with erdafitinib should be avoided.
Asunto(s)
Área Bajo la Curva , Carbamazepina , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Voluntarios Sanos , Humanos , Adulto , Masculino , Femenino , Carbamazepina/farmacología , Carbamazepina/farmacocinética , Carbamazepina/administración & dosificación , Adulto Joven , Citocromo P-450 CYP3A/metabolismo , Persona de Mediana Edad , Inductores del Citocromo P-450 CYP3A/farmacología , Citocromo P-450 CYP2C9/metabolismo , Pirazoles/farmacocinética , Pirazoles/efectos adversos , Pirazoles/administración & dosificación , Pirazoles/farmacología , Quinoxalinas/farmacocinética , Quinoxalinas/efectos adversos , Quinoxalinas/administración & dosificación , Quinoxalinas/farmacología , Administración Oral , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidoresRESUMEN
A population pharmacokinetic (PK)-pharmacodynamic (PD) model was developed using data from 345 patients with cancer. The population PK-PD model evaluated the effect of erdafitinib total and free plasma concentrations on serum phosphate concentrations after once-daily oral continuous (0.5-12 mg) and intermittent (10-12 mg for 7 days on/7 days off) dosing, and investigated the potential covariates affecting erdafitinib-related changes in serum phosphate levels. Phosphate is used as a biomarker for erdafitinib's efficacy and safety: increases in serum phosphate were observed after dosing with erdafitinib, which were associated with fibroblast growth factor receptor target engagement via inhibition of renal fibroblast growth factor 23-mediated signaling. PK-PD model-based simulations were performed to assess the approved PD-guided dosing algorithm of erdafitinib (8 mg once-daily continuous dosing, with up-titration to 9 mg based on phosphate levels [<5.5 mg/dl] and tolerability at 14-21 days of treatment). The serum phosphate concentrations increased after the first dose and reached near maximal level after 14 days of continuous treatment. Serum phosphate increased with erdafitinib free drug concentrations: doubling the free concentration resulted in a 1.8-fold increase in drug-related phosphate changes. Dose adjustment after at least 14 days of dosing was supported by achievement of >95% maximal serum phosphate concentration. The peak-to-trough fluctuation within a dosing interval was limited for serum phosphate concentrations (5.68-5.65 mg/dl on Day 14), supporting phosphate monitoring at any time relative to dosing. Baseline phosphate was higher in women, otherwise, none of the investigated covariate-parameter relationships were considered clinically relevant. Simulations suggest that the starting dose of 8-mg with up-titration to 9-mg on Days 14-21 maximized the number of patients within the target serum phosphate concentrations (5.5-7 mg/dl) while limiting the number of treatment interruptions. The findings from the PK-PD model provided a detailed understanding of the erdafitinib concentration-related phosphate changes over time, which supports erdafitinib's dosing algorithm.
Asunto(s)
Neoplasias , Pirazoles , Femenino , Humanos , Neoplasias/tratamiento farmacológico , Fosfatos/uso terapéutico , Pirazoles/farmacocinética , Quinoxalinas/farmacocinéticaRESUMEN
PURPOSE: Erdafitinib (JNJ-42756493, BALVERSA) is a tyrosine kinase inhibitor indicated for the treatment of advanced urothelial carcinoma. In this work, a translational model-based approach to inform the choice of the doses in phase 1 trials is illustrated. METHODS: A pharmacokinetic (PK) model was developed to describe the time course of erdafitinib plasma concentrations in mice and rats. Data from multiple xenograft studies in mice and rats were analyzed using the Simeoni tumor growth inhibition (TGI) model. The model parameters were used to derive a range of erdafitinib exposures that might inform the choice of the doses in oncology phase 1 trials. Conversion of exposures to doses was based on preliminary PK assessments from the first-in human (FIH) study. RESULTS: A one-compartment PK disposition model, with linear absorption and dose-dependent clearance, adequately described the PK data in both mice and rats via an allometric scaling approach. The TGI model was able to describe tumor growth dynamics, providing quantitative measurements of erdafitinib antitumor potency in mice and rats. Based on these estimates, ranges of efficacious unbound concentration were identified for erdafitinib in mice (0.642-5.364 µg/L) and rats (0.782-2.565 µg/L). Based on the FIH data, it was possible to transpose exposures into doses and doses of above 4 mg/day provided erdafitinib exposures associated with significant TGI in animals. The findings were in agreement with the results of the FIH trial, in which the first hints of clinical activities were observed at 6 mg. CONCLUSION: The successful modeling exercise of erdafitinib preclinical data showed how translational PK-PD modeling might be a tool to help to inform the choice of the doses in FIH studies.
Asunto(s)
Pirazoles/administración & dosificación , Pirazoles/farmacocinética , Quinoxalinas/administración & dosificación , Quinoxalinas/farmacocinética , Investigación Biomédica Traslacional/métodos , Animales , Ensayos Clínicos Fase I como Asunto , Humanos , Ratones Desnudos , Modelos Biológicos , Pirazoles/sangre , Quinoxalinas/sangre , Ratas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The three pan-genotypic HCV NS3/4A protease inhibitors (PIs) currently in clinical use-grazoprevir, glecaprevir, and voxilaprevir-are quinoxaline-based P2-P4 macrocycles and thus exhibit similar resistance profiles. Using our quinoxaline-based P1-P3 macrocyclic lead compounds as an alternative chemical scaffold, we explored structure-activity relationships (SARs) at the P2 and P4 positions to develop pan-genotypic PIs that avoid drug resistance. A structure-guided strategy was used to design and synthesize two series of compounds with different P2 quinoxalines in combination with diverse P4 groups of varying sizes and shapes, with and without fluorine substitutions. Our SAR data and cocrystal structures revealed the interplay between the P2 and P4 groups, which influenced inhibitor binding and the overall resistance profile. Optimizing inhibitor interactions in the S4 pocket led to PIs with excellent antiviral activity against clinically relevant PI-resistant HCV variants and genotype 3, providing potential pan-genotypic inhibitors with improved resistance profiles.
Asunto(s)
Antivirales/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Compuestos Macrocíclicos/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Quinoxalinas/uso terapéutico , Animales , Antivirales/síntesis química , Antivirales/metabolismo , Antivirales/farmacocinética , Cristalografía por Rayos X , Farmacorresistencia Viral/efectos de los fármacos , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/metabolismo , Compuestos Macrocíclicos/farmacocinética , Masculino , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/farmacocinética , Unión Proteica , Quinoxalinas/síntesis química , Quinoxalinas/metabolismo , Quinoxalinas/farmacocinética , Ratas Sprague-Dawley , Serina Proteasas/metabolismo , Relación Estructura-Actividad , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismoRESUMEN
Erdafitinib is a potent oral pan-fibroblast growth factor receptor inhibitor being developed as oncology drug for patients with alterations in the fibroblast growth factor receptor pathway. Erdafitinib binds preferentially to α1-acid glycoprotein (AGP) and is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. This article describes a physiologically based pharmacokinetic (PBPK) model for erdafitinib to assess the drug-drug interaction (DDI) potential of CYP3A4 and CYP2C9 inhibitors and CYP3A4/CYP2C9 inducers on erdafitinib pharmacokinetics (PK) in patients with cancer exhibiting higher AGP levels and in populations with different CYP2C9 genotypes. Erdafitinib's DDI potential as a perpetrator for transporter inhibition and for time-dependent inhibition and/or induction of CYP3A was also evaluated. The PBPK model incorporated input parameters from various in vitro and clinical PK studies, and the model was verified using a clinical DDI study with itraconazole and fluconazole. Erdafitinib clearance in the PBPK model consisted of multiple pathways (CYP2C9/3A4, renal, intestinal; additional hepatic clearance), making the compound less susceptible to DDIs. In poor-metabolizing CYP2C9 populations carrying the CYP2C9*3/*3 genotype, simulations shown clinically relevant increase in erdafitinib plasma concentrations. Simulated luminal and enterocyte concentration showed potential risk of P-glycoprotein inhibition with erdafitinib in the first 5 h after dosing, and simulations showed this interaction can be avoided by staggering erdafitinib and digoxin dosing. Other than a simulated ~ 60% exposure reduction with strong CYP3A/2C inducers such as rifampicin, other DDI liabilities were minimal and considered not clinically relevant.
Asunto(s)
Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Modelos Biológicos , Pirazoles/farmacocinética , Quinoxalinas/farmacocinética , Antineoplásicos/farmacocinética , Citocromo P-450 CYP2C9/efectos de los fármacos , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP3A/efectos de los fármacos , Citocromo P-450 CYP3A/genética , Inductores de las Enzimas del Citocromo P-450/farmacología , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Interacciones Farmacológicas , Genotipo , Humanos , Orosomucoide/metabolismoRESUMEN
There is an urgent need to design new anticancer agents that can prevent cancer cell proliferation even with minimal side effects. Accordingly, two new series of 3-methylquinoxalin-2(1H)-one and 3-methylquinoxaline-2-thiol derivatives were designed to act as VEGFR-2 inhibitors. The designed derivatives were synthesised and evaluated in vitro as cytotoxic agents against two human cancer cell lines namely, HepG-2 and MCF-7. Also, the synthesised derivatives were assessed for their VEGFR-2inhibitory effect. The most promising member 11e were further investigated to reach a valuable insight about its apoptotic effect through cell cycle and apoptosis analyses. Moreover, deep investigations were carried out for compound 11e using western-plot analyses to detect its effect against some apoptotic and apoptotic parameters including caspase-9, caspase-3, BAX, and Bcl-2. Many in silico investigations including docking, ADMET, toxicity studies were performed to predict binding affinity, pharmacokinetic, drug likeness, and toxicity of the synthesised compounds. The results revealed that compounds 11e, 11g, 12e, 12g, and 12k exhibited promising cytotoxic activities (IC50 range is 2.1 - 9.8 µM), comparing to sorafenib (IC50 = 3.4 and 2.2 µM against MCF-7 and HepG2, respectively). Moreover, 11b, 11f, 11g, 12e, 12f, 12g, and 12k showed the highest VEGFR-2 inhibitory activities (IC50 range is 2.9 - 5.4 µM), comparing to sorafenib (IC50 = 3.07 nM). Additionally, compound 11e had good potential to arrest the HepG2 cell growth at G2/M phase and to induce apoptosis by 49.14% compared to the control cells (9.71%). As well, such compound showed a significant increase in the level of caspase-3 (2.34-fold), caspase-9 (2.34-fold), and BAX (3.14-fold), and a significant decrease in Bcl-2 level (3.13-fold). For in silico studies, the synthesised compounds showed binding mode similar to that of the reference compound (sorafenib).
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Quinoxalinas/síntesis química , Quinoxalinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Quinoxalinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
As a continuation of our research on antimycobacterial agents, a series of novel quinoxaline-1,4-di-N-oxides (QdNOs) containing various nitrogenous heterocyclic moieties at the R6 position were designed and synthesized. Antimycobacterial activities, as well as the cytotoxic effects, of the compounds were assayed. Four compounds (6b, 6f, 6n, and 6o), characterized by 2-carboxylate ethyl or benzyl ester, 6-imidazolyl or 1,2,4-triazolyl, and a 7-fluorine group, exhibited the most potent antimycobacterial activity against M.tb strain H37Rv (MIC ≤ 0.25 µg/mL) with low toxicity in VERO cells (SI = 169.3-412.1). Compound 6o also exhibited excellent antimycobacterial activity in an M.tb-infected macrophage model and was selected for further exploration of the mode of antimycobacterial action of QdNOs. The results showed that compound 6o was capable of disrupting membrane integrity and disturbing energy homeostasis in M.tb. Furthermore, compound 6o noticeably increased cellular ROS levels and, subsequently, induced autophagy in M.tb-infected macrophages, possibly indicating the pathways of QdNOs-mediated inhibition of intracellular M.tb replication. The in vivo pharmacokinetic (PK) profiles indicated that compounds 6o was acceptably safe and possesses favorable PK properties. Altogether, these findings suggest that compound 6o is a promising antimycobacterial candidate for further research.
Asunto(s)
Antituberculosos/farmacología , Autofagia/efectos de los fármacos , Macrófagos/microbiología , Mycobacterium tuberculosis/efectos de los fármacos , Quinoxalinas/química , Animales , Antituberculosos/química , Antituberculosos/farmacocinética , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Evaluación Preclínica de Medicamentos , Semivida , Pruebas de Sensibilidad Microbiana , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mycobacterium tuberculosis/fisiología , Óxidos/química , Quinoxalinas/farmacocinética , Quinoxalinas/farmacología , Ratas , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Células VeroRESUMEN
Cyadox (CYA), a 1,4-dioxide quinoxaline, is a safe and effective antibacterial agent with potential use in food-producing animals. The aim of this study was to compare the pharmacokinetics of CYA (Cy0) and its main metabolites [bisdeoxycyadox (Cy1), 4-desoxycyadox (Cy2), N-(quinoxaline-2-methyl)-cyanide acetyl hydrazine (Cy4), quinoxaline-2-carboxylic acid (Cy6), and 2-hydromethyl-3-hydroxy-quinoxaline (Cy12)] after oral administration at three dosages in pigs, chickens, carps, and rats. The concentration vs. time profile in plasma after single oral administration indicated that CYA was rapidly dissociated into its metabolites and showed the widest distribution in all animals, with the highest apparent volume of distribution. Cy0 and Cy6 persisted for the longest time at lower concentration. Cy1and Cy4 concentration was the highest in pig and rat plasma, while Cy1 was undetectable in chickens, and Cy4 was undetectable in carps following administration at three dosages. Different dosage of the CYX and its metabolites had no significant effect on wash-out period. This study revealed obvious species-specific differences in the kinetic behavior of CYA and its metabolites, which may be related to clinical efficacy and toxicity. Our results would facilitate the judicious use of CYA in different animals.
Asunto(s)
Antibacterianos/farmacocinética , Drogas Veterinarias/farmacocinética , Administración Oral , Animales , Antibacterianos/administración & dosificación , Carpas , Pollos , Femenino , Masculino , Quinoxalinas/administración & dosificación , Quinoxalinas/farmacocinética , Ratas , Especificidad de la Especie , Sus scrofa , Drogas Veterinarias/administración & dosificaciónRESUMEN
BACKGROUND AND AIMS: Glecaprevir/pibrentasvir (GLE/PIB) has shown high efficacy and safety in chronic HCV-infected adults and adolescents; data in children were limited. DORA part 2 is a phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics, efficacy, and safety of a pediatric formulation of GLE and PIB in children ages 3 to < 12 years. APPROACH AND RESULTS: Children with chronic HCV infection, genotype 1-6, with or without compensated cirrhosis, were divided into three cohorts by age-cohort 2 (9 to < 12 years), cohort 3 (6 to < 9 years), and cohort 4 (3 to < 6 years)-and given weight-based doses of GLE and PIB for 8, 12, or 16 weeks. Primary endpoints were sustained virologic response at posttreatment week 12 (SVR12) and steady-state exposure; secondary endpoints were rates of persistent viremia, relapse, and reinfection. Safety and laboratory abnormalities were assessed. Final pediatric dosages determined to be efficacious were 250 mg GLE + 100 mg PIB (in children weighing ≥ 30 to < 45 kg), 200 mg GLE + 80 mg PIB (≥ 20 to < 30 kg), and 150 mg GLE + 60 mg PIB (12 to < 20 kg). Of 80 participants enrolled and dosed, 96% (77/80) achieved SVR12. One participant, on the initial dose ratio, relapsed by posttreatment week 4; no participants had virologic failures on the final dose ratio of GLE 50 mg/PIB 20 mg. Two nonresponders prematurely discontinued the study. Most adverse events (AEs) were mild; no drug-related serious AEs occurred. Pharmacokinetic exposures were comparable to those of adults. CONCLUSIONS: A pediatric formulation of GLE/PIB was highly efficacious and well tolerated in chronic HCV-infected children 3 to < 12 years old.
Asunto(s)
Antivirales/farmacocinética , Bencimidazoles/farmacocinética , Hepatitis C Crónica/tratamiento farmacológico , Pirrolidinas/farmacocinética , Quinoxalinas/farmacocinética , Sulfonamidas/farmacocinética , Antivirales/administración & dosificación , Antivirales/efectos adversos , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Niño , Preescolar , Combinación de Medicamentos , Femenino , Técnicas de Genotipaje , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/virología , Humanos , Masculino , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Quinoxalinas/administración & dosificación , Quinoxalinas/efectos adversos , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Resultado del TratamientoRESUMEN
Erdafitinib is a recently approved fibroblast growth factor receptor (FGFR) inhibitor. It is the first treatment targeting susceptible FGFR genetic alterations for patients with metastatic bladder cancer. A simple validated HPLC-UV method was developed for the determination of erdafitinib in mouse plasma. Erdafitinib and internal standard (rivaroxaban) were efficiently separated on Eclipse plus C18 column (4.6 × 100 mm, 3.5 µm). The mobile phase consisted of acetonitrile and 0.01 M ammonium acetate aqueous solution, adjusted to pH 4.4 with acetic acid (26:74, v/v) and it was eluted isocratically at a flow rate of 1.2 mL/min. The UV detection was at 292 nm and the total run time for each sample was 11 min. The method linearity was validated over the range of 0.05-2.00 µg/mL (r2 ≥ 0.9992) and the lower limit of quantification (LLOQ) was 0.05 µg/mL. The within-run and between-run accuracies were 98.56 and 99.24%, respectively while the CV of the method precision did not exceed 6.52%. Plasma samples were extracted using a solid phase extraction procedure and the extraction recoveries were 97.90 ± 4.58%. The method was optimized for the sensitive determination of the studied drug in mouse plasma and was successfully applied to its pharmacokinetic studies.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Pirazoles/sangre , Pirazoles/farmacocinética , Quinoxalinas/sangre , Quinoxalinas/farmacocinética , Animales , Límite de Detección , Modelos Lineales , Ratones , Pirazoles/química , Quinoxalinas/química , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Many people infected with hepatitis C virus have comorbidities, including hypercholesterolemia, that are treated with statins. In this study, we evaluated the drug-drug interaction potential of the hepatitis C virus inhibitors elbasvir (EBR) and grazoprevir (GZR) with statins. Pitavastatin, rosuvastatin, pravastatin, and atorvastatin are substrates of organic anion-transporting polypeptide 1B, whereas rosuvastatin and atorvastatin are also breast cancer resistance protein substrates. METHODS: Three open-label, phase I clinical trials in healthy adults were conducted with multiple daily doses of oral GZR or EBR/GZR and single oral doses of statins. Trial 1: GZR 200 mg plus pitavastatin 10 mg. Trial 2: Part 1, GZR 200 mg plus rosuvastatin 10 mg, then EBR 50 mg/GZR 200 mg plus rosuvastatin 10 mg; Part 2, EBR 50 mg/GZR 200 mg plus pravastatin 40 mg. Trial 3: EBR 50 mg/GZR 200 mg plus atorvastatin 10 mg. RESULTS: Neither GZR nor EBR pharmacokinetics were meaningfully affected by statins. Coadministration of EBR/GZR did not result in clinically relevant changes in the exposure of pitavastatin or pravastatin. However, EBR/GZR increased exposure to rosuvastatin (126%) and atorvastatin (94%). Coadministration of statins plus GZR or EBR/GZR was generally well tolerated. CONCLUSIONS: Although statins do not appreciably affect EBR or GZR pharmacokinetics, EBR/GZR can impact the pharmacokinetics of certain statins, likely via inhibition of breast cancer resistance protein but not organic anion-transporting polypeptide 1B. Coadministration of EBR/GZR with pitavastatin or pravastatin does not require adjustment of either dose of statin, whereas the dose of rosuvastatin and atorvastatin should be decreased when coadministered with EBR/GZR.
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Amidas/farmacocinética , Antivirales/farmacocinética , Benzofuranos/farmacocinética , Carbamatos/farmacocinética , Ciclopropanos/farmacocinética , Imidazoles/farmacocinética , Quinoxalinas/farmacocinética , Sulfonamidas/farmacocinética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Adolescente , Adulto , Atorvastatina/farmacocinética , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Pravastatina/farmacocinética , Quinolinas/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Adulto JovenRESUMEN
Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are involved in the disposition of a variety of commonly prescribed drugs. The evaluation of OATP1B1/1B3 inhibition potential by investigational drugs is of interest during clinical drug development due to various adverse events associated with increased exposures of their substrates. Regulatory guidance documents on the in vitro assessment of OATP1B1/1B3 inhibition potential are conservative with up to a third of predictions resulting in false positives. This work investigated the utility of OATP1B1/1B3 endogenous biomarkers, coproporphyrin (CP)-I and CP-III, to assess clinical inhibition of OATP1B1/1B3 and potentially eliminate the need for prospective clinical drug-drug interaction (DDI) studies. Correlations between CP-I exposures and various OATP1B1 static DDI predictions were also evaluated. Glecaprevir/pibrentasvir (GLE/PIB) 300/120 mg fixed-dose combination is known to cause clinical inhibition of OATP1B1/1B3. In a clinical study evaluating the relative bioavailability of various formulations of GLE/PIB regimen, CP-I peak plasma concentration (Cmax ) ratio and 0-16-hour area under the concentration-time curve (AUC0-16 ) ratio relative to baseline increased with increasing GLE exposures, whereas there was a modest correlation between GLE exposure and CP-III Cmax ratio but no correlation with CP-III AUC0-16 ratio. This suggests that CP-I is superior to CP-III as an endogenous biomarker for evaluation of OATP1B1 inhibition. There was a significant correlation between CP-I and GLE Cmax (R2 = 0.65; P < 0.001) across individual subjects. Correlation analysis between GLE OATP1B1 R values and CP-I exposures (Cmax ratio and AUC0-16 ratio) suggests that an R value of > 3 can predict a biologically meaningful inhibition of OATP1B1 when the inhibitor clinical pharmacokinetic parameters are available.
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Bencimidazoles/farmacocinética , Biomarcadores Farmacológicos/sangre , Coproporfirinas/sangre , Transportador 1 de Anión Orgánico Específico del Hígado/antagonistas & inhibidores , Pirrolidinas/farmacocinética , Quinoxalinas/farmacocinética , Sulfonamidas/farmacocinética , Adulto , Área Bajo la Curva , Bencimidazoles/administración & dosificación , Disponibilidad Biológica , Biomarcadores Farmacológicos/metabolismo , Coproporfirinas/metabolismo , Estudios Cruzados , Combinación de Medicamentos , Interacciones Farmacológicas , Monitoreo de Drogas/métodos , Femenino , Voluntarios Sanos , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pirrolidinas/administración & dosificación , Quinoxalinas/administración & dosificación , Sulfonamidas/administración & dosificación , Adulto JovenRESUMEN
Cancer exhibits diverse heterogeneity with a complicated molecular basis that usually harbors genetic and epigenetic abnormality, which poses a big challenge for single-target agents. In the current work, we proposed a hybrid strategy by incorporating pharmacophores that bind to the acetylated lysine binding pocket of BET proteins with a typical kinase hinge binder to generate novel polypharmacological inhibitors of BET and kinases. Through elaborating the core structure of 6-(pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-one, we demonstrated that this rational design can produce high potent inhibitors of CDK9 and BET proteins. In this series, compound 40 was identified as the potential lead compound with balanced activities of BRD4 (IC50 = 12.7 nM) and CDK9 (IC50 = 22.4 nM), as well as good antiproliferative activities on a small cancer cell panel. Together, the current study provided a new method for the discovery of bromodomain and kinase dual inhibitors rather than only being discovered by serendipity.
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Diseño de Fármacos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Quinoxalinas/química , Quinoxalinas/farmacología , Animales , Proteínas de Ciclo Celular/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Descubrimiento de Drogas , Humanos , Ratones , Modelos Moleculares , Dominios Proteicos , Inhibidores de Proteínas Quinasas/farmacocinética , Quinoxalinas/farmacocinética , Relación Estructura-Actividad , Factores de Transcripción/antagonistas & inhibidoresRESUMEN
PURPOSE: Fixed-dose combination glecaprevir (GLE) 300 mg + pibrentasvir (PIB) 120 mg is an orally administered once daily antiviral regimen approved for the treatment of hepatitis C virus (HCV) infection. The objective of this study was to evaluate the potential for cardiac repolarization following GLE + PIB administration in healthy adults. METHODS: This placebo- and active-controlled, randomized, single-dose, 4-period, 4-sequence crossover study enrolled 48 healthy subjects. The doses of GLE 400 mg + PIB 120 mg were selected to provide exposures comparable to those with the doses that are therapeutic in the HCV-infected population, GLE 300 mg + PIB 120 mg. The doses of GLE 600 mg + PIB 240 mg were selected to provide supratherapeutic exposures without exceeding the exposures of the GLE + PIB maximal tolerated doses. Moxifloxacin 400 mg (active control/open label) was used for confirming the sensitivity of the ECG assay in detecting QTc prolongation. Time-matched plasma concentrations and triplicate ECGs were obtained on treatment days -1 and 1. The primary end point was time-matched, placebo-corrected, baseline-adjusted Fridericia-corrected QT interval (ΔΔQTcF). Pharmacokinetic-pharmacodynamic analyses characterized the relationship between GLE and PIB plasma concentrations and ΔΔQTcF using a linear regression model and linear mixed-effects model. Findings from categorical analyses of ECG-interval data were also summarized. Tolerability was evaluated through adverse-events monitoring, physical examination including vital sign measurements, ECGs, and laboratory tests. FINDINGS: A total of 48 subjects (22 women [46%], 26 men [54%]), were enrolled in the study, and 47 subjects completed all 4 periods. None of the subjects had a change from baseline in QTcF interval of >30 msec or an absolute QTcF interval of >450 msec. Peak ΔΔQTcF values observed at 5 h postdose (Tmax) were 2.9 msec (upper 95% confidence limit, 4.9 msec) with the therapeutic dose and 3.1 msec (upper 95% confidence limit, 5.1 msec) with the supratherapeutic dose, with both upper 95% confidence limits well below the 10-msec threshold. Assay sensitivity was confirmed by peak ΔΔQTcF in the positive control (12.8 ms at 2 h postdose). No statistically significant GLE or PIB concentration-dependent effects on ΔΔQTcF were observed. Headache and skin irritation from ECG electrodes were the most commonly reported AEs. No clinically significant vital sign measurements, ECG findings, or laboratory measurements were observed. There were no patterns of T- and U-wave morphologic abnormalities. IMPLICATIONS: The fixed-dose combination regimen of GLE/PIB does not prolong the QTc interval. ClinicalTrials.gov identifier.
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Ácidos Aminoisobutíricos/administración & dosificación , Bencimidazoles/administración & dosificación , Ciclopropanos/administración & dosificación , Frecuencia Cardíaca/efectos de los fármacos , Corazón/efectos de los fármacos , Lactamas Macrocíclicas/administración & dosificación , Leucina/análogos & derivados , Prolina/análogos & derivados , Quinoxalinas/administración & dosificación , Sulfonamidas/administración & dosificación , Adulto , Ácidos Aminoisobutíricos/sangre , Ácidos Aminoisobutíricos/farmacocinética , Bencimidazoles/sangre , Bencimidazoles/farmacocinética , Estudios Cruzados , Ciclopropanos/sangre , Ciclopropanos/farmacocinética , Método Doble Ciego , Combinación de Medicamentos , Electrocardiografía/efectos de los fármacos , Femenino , Voluntarios Sanos , Corazón/fisiología , Humanos , Lactamas Macrocíclicas/sangre , Lactamas Macrocíclicas/farmacocinética , Leucina/administración & dosificación , Leucina/sangre , Leucina/farmacocinética , Síndrome de QT Prolongado , Masculino , Persona de Mediana Edad , Prolina/administración & dosificación , Prolina/sangre , Prolina/farmacocinética , Pirrolidinas , Quinoxalinas/sangre , Quinoxalinas/farmacocinética , Método Simple Ciego , Sulfonamidas/sangre , Sulfonamidas/farmacocinética , Adulto JovenRESUMEN
The use of nanocarriers for drug delivery is a strategy aimed to improve therapeutic indices through changes in their pharmacokinetic and pharmacodynamic characteristics. Liposomes are well-investigated nanocarriers for drug delivery to macrophage-targeted therapy, the main hosts of intracellular pathogens of some infectious diseases, such as leishmaniasis. In this study, we developed hyaluronic acid (HA)-coated liposomes by different methods that can encapsulate a new quinoxaline derivative, the LSPN331, to increase its solubility and improve its bioavailability. The surface modification of liposomes and their physicochemical characteristics may depend on the coating method, which may be a critical parameter with regard to the route of administration of the antileishmanial drug. Liposomes with identical phospholipid composition containing the same drug were developed, and different biological responses were verified, and our hypothesis is that it is related to the type of modification of the surface. Different physicochemical characterization techniques (dynamic light scattering, transmission electron microscopy and UV-vis quantification of labeled-HA) were used to confirm the successful modification of liposomes as well as their stability upon storage. The encapsulation of LSPN331 was performed using HPLC method, and the entrapment efficiency (EE%) was satisfatory in all formulations, considering results of similar formulations in the literature. Furthermore, in vitro and in vivo studies were carried out to evaluate the efficacy against the parasite Leishmania amazonensis. The in vitro activity was maintained or even improved and HA-coated liposomes showed the ability to target to the site of action by the proposed routes of administration, topically and intravenously. Both formulations are promising for future tests of antileishmania activity in vivo.
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Leishmania/metabolismo , Leishmaniasis Cutánea/tratamiento farmacológico , Nanopartículas , Quinoxalinas , Animales , Chlorocebus aethiops , Leishmaniasis Cutánea/metabolismo , Leishmaniasis Cutánea/patología , Liposomas , Masculino , Ratones , Ratones Pelados , Nanopartículas/química , Nanopartículas/uso terapéutico , Quinoxalinas/química , Quinoxalinas/farmacocinética , Quinoxalinas/farmacología , Células VeroRESUMEN
INTRODUCTION: Treatment of unresectable or metastatic urothelial carcinoma (UC) has historically relied upon platinum-based chemotherapy and, more recently, immune checkpoint inhibitors. When tumors progress despite those therapies, remaining effective options are limited. AREAS COVERED: In this review, the authors review the advancement in genomic targets in UC, most notably fibroblast growth factor receptor (FGFR). FGFR has been identified as a target in UC as it is commonly genomically altered (activating mutations or fusions), and may be enriched in UC subtypes that are relatively resistant to immune checkpoint blockade. Erdafitinib, a potent and selective inhibitor of FGFRs, represents the first targeted therapy approved for the treatment of UC by virtue of a confirmed response rate of 40% in an open-label, single-armed phase II trial in molecularly selected tumors. The authors provide their expert opinion of its approval and place it in the context of the current and forthcoming treatment strategies for metastatic UC. EXPERT OPINION: The approval of erdafitinib provides clinicians with an important new treatment option for patients with metastatic UC and projects forward into an era of enhanced molecular precision in identifying effective therapies in UC.
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Antineoplásicos/uso terapéutico , Pirazoles/uso terapéutico , Quinoxalinas/uso terapéutico , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Ensayos Clínicos Fase II como Asunto , Humanos , Terapia Molecular Dirigida , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirazoles/farmacocinética , Quinoxalinas/administración & dosificación , Quinoxalinas/efectos adversos , Quinoxalinas/farmacocinética , Receptores de Factores de Crecimiento de Fibroblastos/genética , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
A novel series of [1,2,4]triazolo[4,3-a]quinoxaline derivatives of different heteroaromatization members were synthesized. The newly synthesized molecules were explored for their potential antimicrobial activities against a panel of pathogenic organisms. Among these derivatives, the chalcone compound 6e with a methoxy substituent exhibited broad potent antimicrobial activity against most of the bacterial and fungal strains. Furthermore, the analysis of the SAR disclosed that the linker and terminal aromatic fragments perform critical roles in exerting antibacterial activity. The molecular docking calculations were executed on two of the most bacterial targets, ATP-binding sites of DNA gyrase B, and the folate-binding site of DHFR enzymes. The results presented good binding data to the pockets of both enzymes showing different linkers contributions through the hydrogen-bonding and aromatic stacking interactions that stabilize the compounds in their pockets taking 6e compound as representative of most active analogs. In addition, good pharmacokinetic profiling data for the 6e compound was obtained and compared to reference drugs. Accordingly, our findings suggest that [1,2,4]triazolo[4,3-a]quinoxaline scaffold is an interesting precursor for the design of potent antimicrobial agents with multitarget inhibition.
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Antibacterianos/farmacología , Escherichia coli/enzimología , Antagonistas del Ácido Fólico/farmacología , Quinoxalinas/farmacología , Inhibidores de Topoisomerasa II/farmacología , Antibacterianos/química , Antibacterianos/farmacocinética , Girasa de ADN/metabolismo , Escherichia coli/efectos de los fármacos , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/microbiología , Antagonistas del Ácido Fólico/química , Antagonistas del Ácido Fólico/farmacocinética , Humanos , Modelos Moleculares , Quinoxalinas/química , Quinoxalinas/farmacocinética , Relación Estructura-Actividad , Tetrahidrofolato Deshidrogenasa/metabolismo , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/farmacocinética , Triazoles/química , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
Cyadox (CYX) is a synthetic antibacterial agent of quinoxaline with much lower toxic effects. A safety criterion of CYX for clinical use was established by studying the pharmacokinetics and metabolism of CYX after oral (PO), intramuscular (IM), and intravenous (IV) administration. CYX was administered in six domesticated cats (three males and three females) by PO (40 mg/kg.b.w.), IM (10 mg/kg.b.w.), and IV (10 mg/kg.b.w.) routes in a crossover pattern. Highly sensitive liquid chromatography with ultraviolet detection (HPLC-UV) method was developed for detection of CYX and its metabolites present in plasma, urine, and feces. The bioavailability of CYX after PO and IM routes was 4.37% and 84.4%. The area under curves (AUC), mean resident time (MRT), and clearance (CL) of CYX and its metabolites revealed that CYX quickly metabolized into its metabolites. The total recovery of CYX and its main metabolites was >60% after each route. PO delivery suggesting first pass effect in cats that might make this route suitable for intestinal infection and IM injection could be better choice for systemic infections. Less ability of glucuronidation did not show any impact on CYX metabolism. The findings of present study provide detailed information for evaluation of CYX.