RESUMEN
Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis-related anemia, a negative prognostic factor for survival. Momelotinib is a novel JAK1/JAK2/activin A receptor type 1 (ACVR1) inhibitor approved in the US, European Union, and the UK and is the first JAK inhibitor indicated specifically for patients with myelofibrosis with anemia. Momelotinib not only addresses the splenomegaly and symptoms associated with myelofibrosis by suppressing the hyperactive JAK-STAT (signal transducer and activator of transcription) pathway but also improves anemia and reduces transfusion dependency through ACVR1 inhibition. The recommended dose of momelotinib is 200 mg orally once daily, which was established after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Momelotinib is metabolized primarily by CYP3A4 and excreted as metabolites in feces and urine. Steady-state maximum concentration is 479 ng/mL (CV%, 61%), with a mean AUCtau of 3288 ng.h/mL (CV%, 60%); its major metabolite, M21, is active (≈40% of pharmacological activity of parent), with a metabolite-to-parent AUC ratio of 1.4-2.1. This review describes momelotinib's mechanism of action, detailing how the JAK-STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment.
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Investigación Biomédica Traslacional , Humanos , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/metabolismo , Benzamidas/farmacología , Benzamidas/farmacocinética , Benzamidas/efectos adversos , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Animales , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Transducción de Señal/efectos de los fármacos , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Hidrocarburos Aromáticos con PuentesRESUMEN
Lipid-based formulations (LbFs) have demonstrated success in pharmaceutical applications; however, challenges persist in dissolving entire doses of the drug into defined liquid volumes. In this study, the temperature-induced supersaturation method was employed in LbF to address drug loading and pill burden issues. Supersaturated LbFs (super-LbF) were prepared using the temperature-induced supersaturation method, where the drug load is above its equilibrium solubility. Further, the influence of the drug's physicochemical and thermal characteristics on drug loading and their relevance with an apparent degree of supersaturation (aDS) was studied using two model drugs, ibrutinib and enzalutamide. All the prepared LbFs were evaluated in terms of physical stability, dispersion, and solubilization capacity, as well as pharmacokinetic assessments. Drug re-crystallization was observed in the lipid solution on long-term storage at higher aDS values of 2-2.5. Furthermore, high-throughput lipolysis studies demonstrated a significant decrease in drug concentration across all LbFs (regardless of drug loading) due to a decline in the formulation solvation capacity and subsequent generation of in-situ supersaturation. Further, the in vivo results demonstrated comparable pharmacokinetic parameters between conventional LbF and super-LbF. The short duration of the thermodynamic metastable state limits the potential absorption benefits. However, super-LbFs of Ibr and Enz showed superior profiles, with 1.7-fold and 5.2-fold increased drug exposure compared to their respective crystalline suspensions. In summary, this study emphasizes the potential of temperature-induced supersaturation in LbF for enhancing drug loading and highlights the intricate interplay between drug properties, formulation characteristics, and in vivo performance.
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Adenina , Benzamidas , Química Farmacéutica , Lípidos , Nitrilos , Feniltiohidantoína , Piperidinas , Solubilidad , Temperatura , Nitrilos/química , Nitrilos/administración & dosificación , Piperidinas/química , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Benzamidas/química , Benzamidas/farmacocinética , Adenina/análogos & derivados , Adenina/química , Adenina/administración & dosificación , Feniltiohidantoína/farmacocinética , Feniltiohidantoína/administración & dosificación , Lípidos/química , Animales , Química Farmacéutica/métodos , Composición de Medicamentos/métodos , Masculino , Pirimidinas/farmacocinética , Pirimidinas/química , Pirimidinas/administración & dosificación , Estabilidad de Medicamentos , Cristalización/métodos , Pirazoles/química , Pirazoles/farmacocinética , Pirazoles/administración & dosificación , Lipólisis/efectos de los fármacos , RatasRESUMEN
The compound N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), which combines a selenium atom and a benzamide nucleus in an organic structure, has demonstrated a fast antidepressant-like effect in mice. This action is influenced by the serotonergic system and represents a promising development in the search for novel antidepressant drugs to treat major depressive disorder (MDD), which often resists conventional treatments. This study aimed to further explore the mechanism underlying the antidepressant-like effect of SePB by investigating the involvement of the dopaminergic and noradrenergic systems in the tail suspension test (TST) in mice and evaluating its pharmacokinetic profile in silico. Preadministration of the dopaminergic antagonists haloperidol (0.05 mg/kg, intraperitoneally (i.p.)), a nonselective antagonist of dopamine (DA) receptors, SCH23390 (0.01 mg/kg, subcutaneously (s.c.)), a D1 receptor antagonist, and sulpiride (50 mg/kg, i.p.), a D2/3 receptor antagonist, before SePB (10 mg/kg, intragastrically (i.g.)) prevented the anti-immobility effect of SePB in the TST, demonstrating that these receptors are involved in the antidepressant-like effect of SePB. Administration of the noradrenergic antagonists prazosin (1 mg/kg, i.p.), an α1-adrenergic antagonist, yohimbine (1 mg/kg, i.p.), an α2-adrenergic antagonist, and propranolol (2 mg/kg, i.p.), a ß-adrenergic antagonist, did not block the antidepressant-like effect of SePB on TST, indicating that noradrenergic receptors are not involved in this effect. Additionally, the coadministration of SePB and bupropion (a noradrenaline/dopamine reuptake inhibitor) at subeffective doses (0.1 and 3 mg/kg, respectively) produced antidepressant-like effects. SePB also demonstrated good oral bioavailability and low toxicity in computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. These findings suggest that SePB has potential as a new antidepressant drug candidate with a particular focus on the dopaminergic system.
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Antidepresivos , Benzamidas , Animales , Antidepresivos/farmacología , Antidepresivos/farmacocinética , Benzamidas/farmacología , Benzamidas/farmacocinética , Ratones , Masculino , Antagonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacocinética , Dopamina/metabolismo , Suspensión Trasera , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/farmacocinética , Compuestos de Organoselenio/químicaRESUMEN
Snail and histone deacetylases (HDACs) have an important impact on cancer treatment, especially for their synergy. Therefore, the development of inhibitors targeting both Snail and HDAC might be a promising strategy for the treatment of cancers. In this work, we synthesized a series of Snail/HDAC dual inhibitors. Compound 9n displayed the most potent inhibitory activity against HDAC1 with an IC50 of 0.405 µM, potent inhibition against Snail with a Kd of 0.180 µM, and antiproliferative activity in HCT-116 cell lines with an IC50 of 0.0751 µM. Compound 9n showed a good inhibitory effect on NCI-H522 (GI50 = 0.0488 µM), MDA-MB-435 (GI50 = 0.0361 µM), and MCF7 (GI50 = 0.0518 µM). Docking studies showed that compound 9n can be well docked into the active binding sites of Snail and HDAC. Further studies showed that compound 9n increased histone H4 acetylation in HCT-116 cells and decreased the expression of Snail protein to induce cell apoptosis. These findings highlight the potential for the development of Snail/HDAC dual inhibitors as anti-solid tumour cancer drugs.
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Aminopiridinas/química , Antineoplásicos/síntesis química , Benzamidas/química , Inhibidores Enzimáticos/síntesis química , Histona Desacetilasas/metabolismo , Factores de Transcripción de la Familia Snail/síntesis química , Aminopiridinas/farmacocinética , Animales , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Benzamidas/farmacocinética , Biomarcadores de Tumor , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/farmacocinética , Células HCT116 , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Conformación Proteica , Ratas , Factores de Transcripción de la Familia Snail/farmacocinética , Relación Estructura-ActividadRESUMEN
BACKGROUND: One of the growth mechanisms of castration-resistant prostate cancer (CRPC) is de novo androgen synthesis from intracellular cholesterol, and statins may be able to inhibit this mechanism. In addition, statins have been reported to suppress the expression of androgen receptors (ARs) in prostate cancer cell lines. In this study, we investigated a combination therapy of novel AR antagonists and statin, simvastatin, for CRPC. METHODS: LNCaP, 22Rv1, and PC-3 human prostate cancer cell lines were used. We developed androgen-independent LNCaP cells (LNCaP-LA). Microarray analysis was performed, followed by pathway analysis, and mRNA and protein expression was evaluated by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. Cell viability was determined by MTS assay and cell counts. All evaluations were performed on cells treated with simvastatin and with or without AR antagonists (enzalutamide, apalutamide, and darolutamide). RESULTS: The combination of darolutamide and simvastatin most significantly suppressed proliferation in LNCaP-LA and 22Rv1 cells. In a 22Rv1-derived mouse xenograft model, the combination of darolutamide and simvastatin enhanced the inhibition of cell proliferation. In LNCaP-LA cells, the combination of darolutamide and simvastatin led to reduction in the mRNA expression of the androgen-stimulated genes, KLK2 and PSA; however, this reduction in expression did not occur in 22Rv1 cells. The microarray data and pathway analyses showed that the number of differentially expressed genes in the darolutamide and simvastatin-treated 22Rv1 cells was the highest in the pathway termed "role of cell cycle." Consequently, we focused our efforts on the cell cycle regulator polo-like kinase 1 (PLK1), cyclin-dependent kinase 2 (CDK2), and cell cycle division 25C (CDC25C). In 22Rv1 cells, the combination of darolutamide and simvastatin suppressed the mRNA and protein expression of these three genes. In addition, in PC-3 cells (which lack AR expression), the combination of simvastatin and darolutamide enhanced the suppression of cell proliferation and expression of these genes. CONCLUSIONS: Simvastatin alters the expression of many genes involved in the cell cycle in CRPC cells. Thus, the combination of novel AR antagonists (darolutamide) and simvastatin can potentially affect CRPC growth through both androgen-dependent and androgen-independent mechanisms.
Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Benzamidas/farmacocinética , Proteínas de Ciclo Celular/metabolismo , Quimioterapia Combinada/métodos , Nitrilos/farmacocinética , Feniltiohidantoína/farmacocinética , Neoplasias de la Próstata Resistentes a la Castración , Pirazoles/farmacología , Simvastatina/farmacología , Tiohidantoínas/farmacología , Animales , Recuento de Células/métodos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Masculino , Ratones , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Transducción de Señal/efectos de los fármacos , Análisis de Matrices Tisulares/métodos , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
BACKGROUND: Preclinical studies showed that HC-1119, a deuterated version of enzalutamide, could competitively inhibit androgen binding to androgen receptor by blocking the transmission of androgen receptor signaling pathway as enzalutamide, inducing apoptosis of prostate cancer cells and reducing the proliferation of prostate cancer cells. Animal pharmacokinetic studies also show that deuterization of enzalutamide as HC-1119 could retain the basic properties of mother drug, increases the stability of compounds to metabolic enzymes and the drug exposure in vivo, prolong the half-life and reduce the production of metabolites, which may lead to a better efficacy and safety of HC-1119 compared with enzalutamide. METHODS: To evaluate the pharmacokinetics and safety of HC-1119 and the effects of food on pharmacokinetics in healthy adult Chinese men after single-dose administration of HC-1119. A total of 47 Chinese healthy adult male subjects received HC-1119 soft capsule at a single oral dose of 40, 80, or 160 mg followed on fasting or 160 mg after high-fat meal respectively. HC-1119 prototype and its metabolites M1 and M2 in plasma were collected individually in a total 23 time points. Pharmacokinetics were determined by sensitive LC/MS/MS for dose-proportionality study. RESULTS: In subjects taking HC-1119 soft capsules on fasting, Cmax of HC-1119 prototype increased dose-dependently. Either Cmax and AUC0-∞ of M1 or Cmax of M2 showed statistically significant difference. Dose-proportionality evaluation showed linear pharmacokinetic characteristics in Cmax of HC-1119 prototype, Cmax and AUC0-∞ of M2 in dose range of 40-160 mg. Cmax of HC-1119 was significantly different between the two groups as 160 mg HC-1119 on fasting or after a high-fat diet respectively, while the other parameter were not. HC-1119 and its metabolites M1 and M2 showed a linear dynamic trend. CONCLUSIONS: HC-1119 is expected to have lower clinical dose than the similar drug enzalutamide. The absorption of HC-1119 and the main pharmacokinetic parameters of HC-1119 and its metabolites M1 and M2 were not affected by high-fat diet. The clinical application of HC-1119 soft capsule in the later stage can be recommended for both fasting and postprandial. The safety and tolerance were good in this population.
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Benzamidas , Proliferación Celular/efectos de los fármacos , Estabilidad de Medicamentos , Interacciones Alimento-Droga , Nitrilos , Feniltiohidantoína , Neoplasias de la Próstata , Receptores Androgénicos/metabolismo , Administración Oral , Adulto , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Biomarcadores Farmacológicos/análisis , Cápsulas , China , Relación Dosis-Respuesta a Droga , Semivida , Voluntarios Sanos , Humanos , Masculino , Nitrilos/administración & dosificación , Nitrilos/efectos adversos , Nitrilos/farmacocinética , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/efectos adversos , Feniltiohidantoína/farmacocinética , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Transducción de Señal/efectos de los fármacosRESUMEN
AIMS: Examine relationships between the systemic exposure of acalabrutinib, a highly selective, next-generation Bruton tyrosine kinase inhibitor, and its active metabolite (ACP-5862) vs. efficacy and safety responses in patients with B-cell malignancies who received acalabrutinib as monotherapy or in combination with obinutuzumab. METHODS: For exposure-efficacy analyses, patients with untreated chronic lymphocytic leukaemia were assessed for best overall response, progression-free survival and tumour regression. For exposure-safety analyses, incidences of grade ≥2 adverse events (AEs), grade ≥3 AEs and grade ≥2 events of clinical interest were assessed in patients with B-cell malignancies. Acalabrutinib and ACP-5862 pharmacokinetic (PK) parameter estimates were obtained from population PK modelling. Exposure calculations were based on study dosing regimens. Total active moieties were calculated to account for contributions of ACP-5862 to overall efficacy/safety. RESULTS: A total of 573 patients were included (exposure-efficacy analyses, n = 274; exposure-safety analyses, n = 573). Most patients (93%) received acalabrutinib 100 mg twice daily. Median total active area under the concentration-time curve (AUC24h,ss ) and total active maximal concentration at steady-state (Cmax,ss ) were similar for patients who received acalabrutinib as monotherapy or in combination with obinutuzumab, and for responders and nonresponders. No relationship was observed between AUC24h,ss /Cmax,ss and progression-free survival or tumour regression. Acalabrutinib AUC24h,ss and Cmax,ss were generally comparable across groups regardless of AE incidence. CONCLUSION: No clinically meaningful correlations between acalabrutinib PK exposure and efficacy and safety outcomes were observed. These data support the fixed acalabrutinib dose of 100 mg twice daily in the treatment of patients with B-cell malignancies.
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Leucemia Linfocítica Crónica de Células B , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/uso terapéutico , PirazinasRESUMEN
Background Entrectinib is a CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, ROS1 and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe the in vitro and clinical studies investigating potential entrectinib drug-drug interactions. Methods In vitro studies with human biomaterials assessed the enzymes involved in entrectinib metabolism, and whether entrectinib modulates the activity of the major cytochrome P450 (CYP) enzymes or drug transporter P-glycoprotein. Clinical studies investigated the effect of a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on single-dose entrectinib pharmacokinetics. The effect of entrectinib on sensitive probe substrates for CYP3A4 (midazolam) and P-glycoprotein (digoxin) were also investigated. Results Entrectinib is primarily metabolized by CYP3A4. In vitro, entrectinib is a CYP3A4/5 inhibitor (IC50 2 µM) and a weak CYP3A4 inducer. Entrectinib inhibited P-glycoprotein (IC50 1.33 µM) but is a poor substrate. In healthy subjects, itraconazole increased entrectinib Cmax and AUC by 73% and 504%, respectively, and rifampin decreased entrectinib Cmax and AUC by 56% and 77%, respectively. Single dose entrectinib did not affect midazolam AUC, although Cmax decreased by 34%. Multiple dose entrectinib increased midazolam AUC by 50% and decreased Cmax by 21%. Single dose entrectinib increased digoxin AUC and Cmax by 18% and 28%, respectively, but did not affect digoxin renal clearance. Conclusions Entrectinib is a CYP3A4 substrate and is sensitive to the effects of coadministered moderate/strong CYP3A4 inhibitors and strong inducers, and requires dose adjustment. Entrectinib is a weak inhibitor of CYP3A4 and P-glycoprotein and no dose adjustments are required with CYP3A4/P- glycoprotein substrates.Registration Number (Study 2) NCT03330990 (first posted online November 6, 2017) As studies 1 and 3 are phase 1 trials in healthy subjects, they are not required to be registered.
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Antineoplásicos/farmacocinética , Benzamidas/farmacocinética , Indazoles/farmacocinética , Proteínas Tirosina Quinasas Receptoras/farmacocinética , Adulto , Antineoplásicos/farmacología , Área Bajo la Curva , Benzamidas/farmacología , Inductores del Citocromo P-450 CYP3A/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacología , Interacciones Farmacológicas , Femenino , Semivida , Voluntarios Sanos , Hepatocitos/efectos de los fármacos , Humanos , Indazoles/farmacología , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Proteínas Tirosina Quinasas Receptoras/farmacologíaRESUMEN
This analysis aimed to describe the pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP-5862. A total of 8935 acalabrutinib samples from 712 subjects and 2394 ACP-5862 samples from 304 subjects from 12 clinical studies in patients with B-cell malignancies and healthy subjects were analysed by nonlinear mixed-effects modelling. Acalabrutinib PK was characterized by a 2-compartment model with first-order elimination. The large variability in absorption was adequately described by transit compartment chain and first-order absorption, with between-occasion variability on the mean transit time and relative bioavailability. The PK of ACP-5862 was characterized by a 2-compartment model with first-order elimination, and the formation rate was defined as the acalabrutinib clearance multiplied by the fraction metabolized. Health status, Eastern Cooperative Oncology Group performance status, and coadministration of proton-pump inhibitors were significant covariates. However, none of the investigated covariates led to clinically meaningful changes in exposure, supporting a flat dosing of acalabrutinib.
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Benzamidas , Neoplasias , Benzamidas/farmacocinética , Voluntarios Sanos , Humanos , Modelos Biológicos , Pirazinas/farmacocinéticaRESUMEN
INTRODUCTION: Preclinical evidence suggests the feedforward cytokine loop of interleukin-6/Janus kinases (JAK)/STAT3 plays a role in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance in EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: In this phase 1b study, the JAK1/2 and TANK-binding kinase 1 (TBK1) inhibitor momelotinib was evaluated in combination with erlotinib in patients with EGFR TKI-naive, EGFR-mutated NSCLC. After erlotinib lead-in (50, 75, 100, or 150 mg oral daily [QD]), momelotinib was combined and dose escalated in a 3 + 3 study design. The primary endpoint of maximum tolerated dose (MTD) of momelotinib was determined based on the incidence of dose-limiting toxicities (DLTs) during the first 28-day cycle. Secondary endpoints included efficacy and pharmacokinetics (PK). RESULTS: Eleven patients were enrolled across 3 dose levels of momelotinib (100 mg QD, 200 mg QD, and 100 mg twice daily [BID]). The MTD was momelotinib 200 mg QD in combination with erlotinib. Two DLTs of grade 4 neutropenia without fever and grade 3 diarrhea occurred at momelotinib 100 mg BID. Most common treatment-emergent adverse events included diarrhea, dry skin, fatigue, and decreased appetite; the vast majority being grades 1-2. The overall response rate was 54.5% (90% CI 27.1-80.0; all partial) and median progression-free survival was 9.2 months (90% CI 6.2-12.4). Momelotinib did not affect the PK of erlotinib. CONCLUSIONS: The JAK1/2 and TBK1 inhibitor momelotinib in combination with erlotinib did not appear to enhance benefit over the historical data of erlotinib monotherapy in patients with EGFR-mutated NSCLC. CLINICALTRIALS. GOV IDENTIFIER: NCT02206763.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Benzamidas/administración & dosificación , Benzamidas/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Clorhidrato de Erlotinib/administración & dosificación , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Resultado del TratamientoRESUMEN
BACKGROUND: Entinostat is an oral inhibitor of class I histone deacetylases intended for endocrine therapy-resistant patients with hormone receptor-positive (HR+) advanced or metastatic breast cancer (BC). We examined the safety, efficacy, and pharmacokinetics of entinostat monotherapy and combined entinostat/exemestane in Japanese patients. METHODS: This phase 1 study (3 + 3 dose-escalation design) enrolled postmenopausal women with advanced/metastatic HR+ BC previously treated with nonsteroidal aromatase inhibitors. Dose-limiting toxicities (DLTs) of entinostat monotherapy (3 mg/qw, 5 mg/qw, or 10 mg/q2w) and entinostat+exemestane (5 mg/qw + 25 mg/qd) were assessed. Pharmacokinetics, lysine acetylation (Ac-K), and T-cell activation markers were measured at multiple time points. RESULTS: Twelve patients were enrolled. No DLTs or grade 3-5 adverse events (AEs) occurred. Drug-related AEs (≥ 2 patients) during DLT observation were hypophosphatemia, nausea, and platelet count decreased. Six patients (50%) achieved stable disease (SD) for ≥ 6 months, including one treated for > 19 months. Median progression-free survival was 13.9 months (95% CI 1.9-not calculable); median overall survival was not reached. Area under the plasma concentration-time curve and Ac-K in peripheral blood CD19+ B cells increased dose-proportionally. The changing patterns of entinostat concentrations and Ac-K levels were well correlated. T-cell activation markers increased over time; CD69 increased more in patients with SD ≥ 6 months vs. SD < 6 months. CONCLUSIONS: Entinostat monotherapy and combined entinostat/exemestane were well tolerated in Japanese patients, with no additional safety concerns compared with previous reports. The correlation between pharmacokinetics and Ac-K in peripheral blood CD19+ B cells, and also T-cell activation markers, merits further investigation. TRIAL REGISTRATION: JAPIC Clinical Trial Information, JapicCTI-153066 . Registered 12 November 2015. ClinicalTrials.gov, NCT02623751 . Registered 8 December 2015.
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Androstadienos/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Piridinas/uso terapéutico , Acetilación , Anciano , Androstadienos/efectos adversos , Androstadienos/farmacocinética , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Inhibidores de la Aromatasa/uso terapéutico , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Neoplasias de la Mama/sangre , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Femenino , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Hipofosfatemia/inducido químicamente , Japón , Activación de Linfocitos , Persona de Mediana Edad , Náusea/inducido químicamente , Recuento de Plaquetas , Supervivencia sin Progresión , Piridinas/efectos adversos , Piridinas/farmacocinéticaRESUMEN
Treatment failure or relapse due to tumor escape caused by reduction in target antigen expression has become a challenge in the field of CART therapy. Target antigen density is closely related to the effectiveness of CART therapy, and reduced or lost target antigen expression limits the efficacy of CART therapy and hinders the durability of CAR T cells. Epigenetic drugs can regulate histones for molecular modifications to regulate the transcriptional, translational and post-translational modification processes of target agents, and we demonstrated for the first time the role in regulating CD22 expression and its effect on the efficacy of CD22 CART. In this paper, we found that Chidamide promoted the expression of CD22 on the surface of B-cell tumor cells in vitro and in vivo, and enhanced the function of CD22 CART. As for mechanisms, we demonstrated that Chidamide did not affect CD22 mRNA transcription, but significantly increased the expression of total CD22 protein, indicating that Chidamide may upregulate cell surface CD22 expression by affecting the distribution of CD22 protein. In summary, our results suggest that Chidamide may enhance the efficacy of CD22 CART by inhibiting histone deacetylases to regulate post-transcriptional modifications that affect protein distribution to increase the expression of CD22 on the cell surface.
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Aminopiridinas/farmacocinética , Benzamidas/farmacocinética , Inmunoterapia Adoptiva/métodos , Lectina 2 Similar a Ig de Unión al Ácido Siálico/metabolismo , Aminopiridinas/metabolismo , Linfocitos B/inmunología , Benzamidas/metabolismo , Línea Celular Tumoral , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Inhibidores de Histona Desacetilasas/farmacología , Histonas , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Cultivo Primario de Células , Receptores Quiméricos de Antígenos/inmunología , Lectina 2 Similar a Ig de Unión al Ácido Siálico/efectos de los fármacos , Linfocitos T/inmunología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
New synthetic opioids (NSOs) pose a public health concern since their emergence on the illicit drug market and are gaining increasing importance in forensic toxicology. Like many other new psychoactive substances, NSOs are consumed without any preclinical safety data or any knowledge on toxicokinetic (TK) data. Due to ethical reasons, controlled human TK studies cannot be performed for the assessment of these relevant data. As an alternative animal experimental approach, six pigs per drug received a single intravenous dose of 100 µg/kg body weight (BW) of U-47700 or 1000 µg/kg BW of tramadol to evaluate whether this species is suitable to assess the TK of NSOs. The drugs were determined in serum and whole blood using a fully validated method based on solid-phase extraction and LC-MS/MS. The concentration-time profiles and a population (pop) TK analysis revealed that a three-compartment model best described the TK data of both opioids. Central volumes of distribution were 0.94 L/kg for U-47700 and 1.25 L/kg for tramadol and central (metabolic) clearances were estimated at 1.57 L/h/kg and 1.85 L/h/kg for U-47700 and tramadol, respectively. The final popTK model parameters for pigs were upscaled via allometric scaling techniques. In comparison to published human data, concentration-time profiles for tramadol could successfully be predicted with single species allometric scaling. Furthermore, possible profiles for U-47700 in humans were simulated. The findings of this study indicate that unlike a multiple species scaling approach, pigs in conjunction with TK modeling are a suitable tool for the assessment of TK data of NSOs and the prediction of human TK data.
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Benzamidas/farmacocinética , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Tramadol/farmacocinética , Administración Intravenosa , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/toxicidad , Animales , Benzamidas/toxicidad , Humanos , Drogas Ilícitas/farmacocinética , Drogas Ilícitas/toxicidad , Masculino , Modelos Biológicos , Especificidad de la Especie , Porcinos , Distribución Tisular , Toxicocinética , Tramadol/toxicidadRESUMEN
Aim: The present study aimed to develop a UHPLC-MS/MS method for determination of vistusertib in biological matrix, and to describe the pharmacokinetic behavior of vistusertib in SD rats. Methodology & results: After protein precipitation with acetone and acetonitrile (1:1), the chromatographic separation was achieved on an Agilent Poroshell 120 EC-C18 column and detected with a SCIEX QTRAP 4500 mass spectrometer under positive ionization mode. The developed UHPLC-MS/MS method showed an excellent linearity within the range of 1.0-3000 ng/ml with good accuracy and precision. Vistusertib showed a rapid absorption and reached the maximum concentration of 3532.2 ± 678.0 ng/ml 20-30 min after oral administration in Sprague-Dawley rats. Conclusion: The established analytical method was fast, sensitive and robust, and successfully applied to describe the pharmacokinetic behavior of vistusertib following an oral administration in rats.
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Benzamidas/farmacocinética , Benzamidas/uso terapéutico , Cromatografía Líquida de Alta Presión/métodos , Morfolinas/farmacocinética , Morfolinas/uso terapéutico , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Espectrometría de Masas en Tándem/métodos , Animales , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND AND OBJECTIVE: Entrectinib is a selective inhibitor of ROS1/TRK/ALK kinases, recently approved for oncology indications. Entrectinib is predominantly cleared by cytochrome P450 (CYP) 3A4, and modulation of CYP3A enzyme activity profoundly alters the pharmacokinetics of both entrectinib and its active metabolite M5. We describe development of a combined physiologically based pharmacokinetic (PBPK) model for entrectinib and M5 to support dosing recommendations when entrectinib is co-administered with CYP3A4 inhibitors or inducers. METHODS: A PBPK model was established in Simcyp® Simulator. The initial model based on in vitro-in vivo extrapolation was refined using sensitivity analysis and non-linear mixed effects modeling to optimize parameter estimates and to improve model fit to data from a clinical drug-drug interaction study with the strong CYP3A4 inhibitor, itraconazole. The model was subsequently qualified against clinical data, and the final qualified model used to simulate the effects of moderate to strong CYP3A4 inhibitors and inducers on entrectinib and M5 pharmacokinetics. RESULTS: The final model showed good predictive performance for entrectinib and M5, meeting commonly used predictive performance acceptance criteria in each case. The model predicted that co-administration of various moderate CYP3A4 inhibitors (verapamil, erythromycin, clarithromycin, fluconazole, and diltiazem) would result in an average increase in entrectinib exposure between 2.2- and 3.1-fold, with corresponding average increases for M5 of approximately 2-fold. Co-administration of moderate CYP3A4 inducers (efavirenz, carbamazepine, phenytoin) was predicted to result in an average decrease in entrectinib exposure between 45 and 79%, with corresponding average decreases for M5 of approximately 50%. CONCLUSIONS: The model simulations were used to derive dosing recommendations for co-administering entrectinib with CYP3A4 inhibitors or inducers. PBPK modeling has been used in lieu of clinical studies to enable regulatory decision-making.
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Benzamidas/metabolismo , Benzamidas/farmacocinética , Indazoles/metabolismo , Indazoles/farmacocinética , Simulación por Computador , Inductores del Citocromo P-450 CYP3A/metabolismo , Inductores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Interacciones Farmacológicas/fisiología , HumanosRESUMEN
PURPOSE: Entrectinib (ROZLYTREK®) is a CNS-active, potent, and selective inhibitor of ROS1, TRK A/B/C, and ALK kinase activity. It was recently approved for the treatment of ROS1-positive non-small cell lung cancer and NTRK gene fusion-positive solid tumors. The main objective of this analysis was to characterize the pharmacokinetics (PK) of entrectinib and its main active metabolite, M5. METHODS: A total of 276 cancer patients receiving oral entrectinib were included in the analysis. A model-based population approach was used to characterize the PK profiles of both entities using NONMEM® 7.4. A joint model captures the PK of both entrectinib and M5. The effects of pH modifiers, formulation, weight, age, and sex on model parameters were assessed. Model performance was evaluated using visual predictive checks (VPCs). RESULTS: The absorption of entrectinib was best described using a sequential zero- and first-order absorption model and the disposition with one-compartment model for each entity with linear elimination. Moderate-to-high between-patient variability was estimated in model parameters (from 30.8% for the apparent clearance of entrectinib to 122% for the first-order absorption rate constant). Theory-based allometric scaling using body weight on clearances and volumes and a 28% lower relative bioavailability of the F1 formulation in pediatric patients were retained in the model. The VPC confirmed the good predictive performance of the PopPK model. CONCLUSIONS: A robust population PK model was built and qualified for entrectinib and M5, describing linear PK for both entities. This model was used to support the ROZLYTREK® new drug application.
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Benzamidas/administración & dosificación , Benzamidas/farmacocinética , Indazoles/administración & dosificación , Indazoles/farmacocinética , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Pronóstico , Distribución Tisular , Adulto JovenRESUMEN
Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK-degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS-4718. X-ray crystallography revealed the molecular basis of the highly cooperative FAK-GSK215-VHL ternary complex, and GSK215 showed differentiated in-vitro pharmacology compared to VS-4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long-lasting effect on FAK levels (≈96â h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK-degradation biology inâ vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.
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Antineoplásicos/farmacología , Quinasa 1 de Adhesión Focal/antagonistas & inhibidores , Proteolisis/efectos de los fármacos , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Dipéptidos/química , Dipéptidos/farmacocinética , Dipéptidos/farmacología , Quinasa 1 de Adhesión Focal/metabolismo , Humanos , Ratones , Estructura Molecular , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Recent studies revealed that the activation of serotonergic 5-HT1A and muscarinic M1, M4, or M5 receptors prevent MK-801-induced cognitive impairments in animal models. In the present study, the effectiveness of the simultaneous activation of 5-HT1A and muscarinic receptors at preventing MK-801-induced cognitive deficits in novel object recognition (NOR) or Y-maze tests was investigated. Activators of 5-HT1A (F15599), M1 (VU0357017), M4 (VU0152100), or M5 (VU0238429) receptors administered at top doses for seven days reversed MK-801-induced deficits in the NOR test, similar to the simultaneous administration of subeffective doses of F15599 (0.05 mg/kg) with VU0357017 (0.15 mg/kg), VU0152100 (0.05 mg/kg), or VU0238429 (1 mg/kg). The compounds did not prevent the MK-801-induced impairment when administered acutely. Their activity was less evident in the Y-maze. Pharmacokinetic studies revealed high brain penetration of F15599 (brain/plasma ratio 620%), which was detected in the frontal cortex (FC) up to 2 h after administration. Decreases in the brain penetration properties of the compounds were observed after acute administration of the combinations, which might have influenced behavioral responses. This negative effect on brain penetration was not observed when the compounds were administered repeatedly. Based on our results, prolonged administration of a 5-HT1A activator with muscarinic receptor ligands may be effective at reversing cognitive decline related to schizophrenia, and the FC may play a critical role in this interaction.
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Colinérgicos/farmacología , Disfunción Cognitiva/tratamiento farmacológico , Corteza Prefrontal/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Agonistas de Receptores de Serotonina/farmacología , Animales , Benzamidas/farmacocinética , Benzamidas/farmacología , Benzamidas/uso terapéutico , Barrera Hematoencefálica/metabolismo , Colinérgicos/farmacocinética , Colinérgicos/uso terapéutico , Disfunción Cognitiva/etiología , Maleato de Dizocilpina/toxicidad , Masculino , Aprendizaje por Laberinto , Ratones , Piperidinas/farmacocinética , Piperidinas/farmacología , Piperidinas/uso terapéutico , Corteza Prefrontal/metabolismo , Piridinas/farmacocinética , Piridinas/farmacología , Piridinas/uso terapéutico , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Receptores Muscarínicos/metabolismo , Receptores de Serotonina/metabolismo , Esquizofrenia/complicaciones , Agonistas de Receptores de Serotonina/farmacocinética , Agonistas de Receptores de Serotonina/uso terapéutico , Tiofenos/farmacocinética , Tiofenos/farmacología , Tiofenos/uso terapéuticoRESUMEN
PURPOSE: CHMFL-KIT-110, a selective c-KIT kinase inhibitor for gastrointestinal stromal tumors (GISTs), possesses a poorly water-soluble, limiting the further development of the drug. This study was to investigate the antitumor efficacy of CHMFL-KIT-110 and CHMFL-KIT-110 solid dispersion (laboratory code: HYGT-110 SD) in GIST tumor xenograft models and to explore the PK/PD relationship of HYGT-110 SD. METHODS: Plasma concentrations of HYGT-110 and HYGT-110 SD were determined by LC-MS/MS in KM mice. Antitumor activity was evaluated by measuring tumor volume and weight in c-KIT-dependent GIST xenograft models. PK/PD relationship was assessed by LC-MS/MS and Western Blot in the GIST-T1 xenografted mice. RESULTS: HYGT-110 exhibited a low oral bioavailability (10.91%) in KM mice. Compared with HYGT-110 treatment, the Cmax and AUC0-t of HYGT-110 SD in mice plasma were substantially increased by 18.81 and 6.76-fold, respectively. HYGT-110 SD (10, 30, and 100 mg/kg/day) also could dose-dependently decrease the tumor volume and weight in the GIST-882 cell-inoculated xenograft mouse models and show 86.35% tumor growth inhibition (TGI) at 28 days at a 25 mg/kg bid dosage in the GIST-T1 cell-inoculated xenograft mouse model. The free concentration of HYGT-110 in plasma was closely correlated with the inhibition of c-KIT phosphorylation levels in tumor tissues. CONCLUSIONS: In comparison with the HPMC formulation, both improved PK and PD characteristics of the solid dispersion formulation of CHMFL-KIT-110 were observed in in vivo animal experiments.
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Antineoplásicos/farmacología , Benzamidas/farmacología , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Ácidos Isonicotínicos/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Benzamidas/administración & dosificación , Benzamidas/farmacocinética , Línea Celular Tumoral , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/patología , Humanos , Inyecciones Intravenosas , Ácidos Isonicotínicos/administración & dosificación , Ácidos Isonicotínicos/farmacocinética , Masculino , Ratones , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-kit/sangre , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: The first-in-class BTK inhibitor ibrutinib has substantially changed the therapeutic landscape of chronic lymphocytic leukemia (CLL). The next-generation BTK inhibitor acalabrutinib is more selective and may have less off-target toxicities as compared to ibrutinib. Acalabrutinib has demonstrated safety and efficacy in CLL and has been approved to treat CLL. AREAS COVERED: Current clinical trials investigated acalabrutinib monotherapy or acalabrutinib-based combination therapies in relapsed/refractory and treatment-naive CLL. Data on the efficacy and safety of acalabrutinib in clinical trials were summarized in this review. The pharmacokinetic and pharmacodynamic data of acalabrutinib were also discussed. EXPERT OPINION: Acalabrutinib selectively inhibits BTK by covalent binding and shows rapid absorption and elimination. Acalabrutinib does not inhibit EGFR, TEC, or ITK and shows fewer off-target toxicities. Completed phase 3 trials have demonstrated that acalabrutinib improves the outcomes of patients with relapsed/refractory CLL and patients with treatment-naive CLL. The phase 3 trial that evaluates acalabrutinib versus ibrutinib has met its primary endpoint. Early phase studies suggested the combinations of acalabrutinib with a CD20 antibody and venetoclax led to high rates of undetectable minimal residual disease in the bone marrow in CLL patients and might provide a fixed-duration therapeutic option for patients with CLL.