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1.
Comput Biol Chem ; 80: 433-440, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31146119

RESUMO

High production cost, instability, low tumor penetration are some of the shortcomings that have characterized and undermined the use of antibodies as a target for Cytotoxic T-lymphocytes associated protein 4 (CTLA-4). Design and discovery of small molecule inhibitors have therefore become a sine qua non in targeting immune proteins implicated in immune disorders. In this study, we utilized a drug repositioning approach to explore the characteristic feature of unrelated proteins to have similar binding sites and the promiscuity of drugs to repurpose an existing drug to target CTLA-4. CTLA-4 and Kallikrein-7 were found to have similar binding sites, we therefore used 1, 3, 6-trisubstituted 1, 4-diazepane-7-ones (TDSO) which is an inhibitor of Kallikrein-7 as our lead compound. High throughput screening using TDSO as a lead compound resulted in 9 hits with ZINC04515726 and ZINC08985213 having the highest binding score. We went ahead to investigate the interaction of these compounds with CTLA-4 by conducting a molecular dynamic simulation. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) estimations revealed that TDSO had the highest binding energy value of -28.51Kcal/mol, with ZINC04515726 and ZINC08985213 having -23.76Kcal/mol and -21.03Kcal/mol respectively. The per-residue decomposition highlighted Tyr24, Ala25, Gly28, Ala30, Tyr53 and Asn72 as having significantly high electrostatic energy contributions and the main contributing residues to the binding of TDSO, ZINC04515726 and ZINC08985213 to Cytotoxic T lymphocytes CTLA-4. Summarily, from the results gathered, we proposed that TDSO can be an effective immune check point small molecule inhibitor against the suppression of T-cell activation, proliferation, and tumor cell eradication.


Assuntos
Azepinas/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Reposicionamento de Medicamentos , Polifarmacologia , Sequência de Aminoácidos , Azepinas/química , Azepinas/farmacocinética , Sítios de Ligação , Antígeno CTLA-4/química , Ensaios de Triagem em Larga Escala , Humanos , Calicreínas/química , Simulação de Dinâmica Molecular , Ligação Proteica
2.
Am J Clin Oncol ; 42(5): 413-420, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30973373

RESUMO

OBJECTIVES: Pazopanib is a multikinase angiogenesis inhibitor. Alisertib is a highly selective inhibitor of mitotic Aurora A kinase. There is preclinical evidence that mitosis-targeting agents exhibit antiangiogenic effects. Thus, the combination of these 2 agents may have a synergistic effect on tumor vasculature. The primary objective of this study is to determine the optimal tolerated dose (OTD) for alisertib and pazopanib. MATERIALS AND METHODS: This phase 1b study evaluated the OTD of alisertib twice a day, on days 1 to 7 with pazopanib, once a day, continuously in a 21-day cycle, both taken orally. Disease response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 every 2 cycles. OTD cohort was expanded to assure safety and perform pharmacokinetics analysis. RESULTS: A total of 27 patients received treatment. Seventy-seven percent of the patients had received at least 3 prior chemotherapy regimens. Dose-limiting toxicities occurred in dose level (DL) 2+ (grade 4 thrombocytopenia and grade 3 mucositis) and DL 3 (grade 3 liver transaminases elevation and grade 3 abdominal pain). The OTD was determined to be DL 2: alisertib 20 mg twice daily and pazopanib 600 mg daily. Pharmacokinetic analysis revealed that clearance of alisertib was reduced by ∼40% in the presence of pazopanib compared with clearance in the absence of pazopanib. Fourteen patients had stable disease and 2 patients had a partial response. CONCLUSIONS: The combination of alisertib with pazopanib demonstrates manageable safety and early clinical evidence of antitumor activity in patients with advanced malignancies (NCT01639911).


Assuntos
Azepinas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Fatores Etários , Idoso , Azepinas/farmacocinética , Estudos de Coortes , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias/patologia , Segurança do Paciente , Pirimidinas/farmacocinética , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Sulfonamidas/farmacocinética , Análise de Sobrevida , Resultado do Tratamento
3.
Clin Drug Investig ; 39(5): 441-451, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30810914

RESUMO

BACKGROUND AND OBJECTIVES: Suvorexant is an orexin receptor antagonist indicated for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. As suvorexant is metabolized primarily by Cytochrome P450 3A (CYP3A), and its pharmacokinetics may be affected by CYP3A modulators, the effects of CYP3A inhibitors (ketoconazole or diltiazem) or an inducer (rifampin [rifampicin]) on the pharmacokinetics, safety, and tolerability of suvorexant were investigated. METHODS: In two Phase I, open-label, fixed-sequence trials (Studies P008 and P038), healthy subjects received a single oral dose of suvorexant followed by co-administration with multiple once-daily doses of strong/moderate CYP3A inhibitors (ketoconazole/diltiazem) or a strong CYP3A inducer (rifampin). Treatments were administered in the morning: suvorexant 4 mg with ketoconazole 400 mg (Study P008; N = 10), suvorexant 20 mg with diltiazem 240 mg (Study P038; N = 20), and suvorexant 40 mg with rifampin 600 mg (Study P038; N = 10). Area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), maximum plasma concentration (Cmax), half-life (t½), and time to Cmax (tmax) were derived from plasma concentrations of suvorexant collected at prespecified time points up to 10 days following CYP3A inhibitor/inducer co-administration. Adverse events (AEs) were recorded. RESULTS: Co-administration with ketoconazole resulted in increased exposure to suvorexant [AUC0-∞: geometric mean ratio (GMR); 90% confidence interval (CI) 2.79 (2.35, 3.31)] while co-administration with diltiazem resulted in a lesser effect [GMR (90% CI): 2.05 (1.82, 2.30)]. Co-administration with rifampin led to a marked decrease (88%) in suvorexant exposure. Consistent with morning administration and known suvorexant pharmacology, somnolence was the most frequently reported AE. CONCLUSIONS: These results are consistent with expectations that strong CYP3A inhibitors and inducers exert marked effects on suvorexant pharmacokinetics. In the context of a limited sample size, single suvorexant doses were generally well tolerated in healthy subjects when co-administered with/without a CYP3A inhibitor/inducer.


Assuntos
Azepinas/farmacocinética , Indutores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Interações Medicamentosas/fisiologia , Antagonistas dos Receptores de Orexina/farmacocinética , Triazóis/farmacocinética , Administração Oral , Adulto , Diltiazem/farmacocinética , Voluntários Saudáveis , Humanos , Cetoconazol/farmacocinética , Masculino , Pessoa de Meia-Idade , Rifampina/administração & dosagem , Adulto Jovem
4.
Invest New Drugs ; 37(4): 666-673, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30397836

RESUMO

Aims This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics and safety of the investigational aurora A kinase inhibitor, alisertib, in three patients with advanced malignancies. Methods Part A; patients received a single 35-mg dose of [14C]-alisertib oral solution (~80 µCi total radioactivity [TRA]). Serial blood, urine, and fecal samples were collected up to 336 h post-dose for alisertib mass balance and pharmacokinetics in plasma and urine by liquid chromatography-tandem mass spectrometry, and mass balance/recovery of [14C]-radioactivity in urine and feces by liquid scintillation counting. Part B; patients received non-radiolabeled alisertib 50 mg as enteric-coated tablets twice-daily for 7 days in 21-day cycles. Results In part A, absorption was fast (median plasma Tmax, 1 h) for alisertib and TRA. Mean plasma t1/2 for alisertib and TRA were 23.4 and 42.0 h, respectively. Mean plasma alisertib/TRA AUC0-inf ratio was 0.45, indicating presence of alisertib metabolites in circulation. Mean TRA blood/plasma AUC0-last ratio was 0.60, indicating preferential distribution of drug-related material in plasma. On average, 87.8% and 2.7% of administered radioactivity was recovered in feces and urine, respectively (total recovery, 90.5% by 14 days post-dose). In part B, patients received a median 3 cycles of alisertib. The most common any-grade adverse events were fatigue and alopecia. Conclusions Findings suggest that alisertib is eliminated mainly via feces, consistent with hepatic metabolism and biliary excretion of drug-related material. Further investigation of alisertib pharmacokinetics in patients with moderate-severe hepatic impairment is warranted to inform dosing recommendations in these patient populations.


Assuntos
Antineoplásicos/farmacocinética , Aurora Quinase A/antagonistas & inibidores , Azepinas/farmacocinética , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Administração Oral , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/urina , Azepinas/efeitos adversos , Azepinas/sangue , Azepinas/urina , Fezes/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/urina , Pirimidinas/efeitos adversos , Pirimidinas/sangue , Pirimidinas/urina
5.
Eur J Pharm Sci ; 127: 276-281, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30439495

RESUMO

The aim of the study was to visualize the penetration modifying effect of laurocapram on the delivery of diazepam and codeine across buccal mucosa by MALDI Mass Spectrometry Imaging (MALDI-MSI). A qualitative ex vivo study was carried out by mounting porcine buccal mucosa in Ussing chamber sliders and applying a pre-treatment of phosphate buffered saline (PBS) or a 50% (v/v) laurocapram:ethanol solution apically before incubation for 1 or 3 h with a 0.1 M diazepam or 0.1 M codeine solution. MALDI-MSI analysis was performed on vertical cryo-sections of porcine buccal mucosa. The analysis provided detailed images of the localisation of the drugs, laurocapram and endogenous lipids in the epithelium and connective tissue. While diazepam in the absence of laurocapram was distributed with a steady concentration gradient through the connective tissue, indicating passive diffusion, pre-treatment with laurocapram fundamentally altered the penetration of diazepam through the buccal mucosa. In the presence of laurocapram, the distribution of diazepam was restricted to areas where laurocapram itself was present, in particular in the outer epithelial cell layers and in certain islands in the connective tissue. In contrast, the penetration of codeine was unaffected by the presence of laurocapram in similar experiments. The co-localization of laurocapram and diazepam indicates a reservoir effect, which has previously been found in diffusion experiments in Ussing chambers. The major difference in the penetration of codeine and diazepam through the buccal mucosa in presence of laurocapram was explained by the physicochemical properties of the drugs. Codeine is characterized by being more hydrophilic than diazepam and was partly charged under the given experimental conditions.


Assuntos
Azepinas/administração & dosagem , Codeína/administração & dosagem , Diazepam/administração & dosagem , Mucosa Bucal/metabolismo , Administração Bucal , Animais , Azepinas/farmacocinética , Codeína/farmacocinética , Diagnóstico por Imagem , Diazepam/farmacocinética , Espectrometria de Massas , Permeabilidade/efeitos dos fármacos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Suínos
6.
J Pharm Biomed Anal ; 163: 17-23, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30273837

RESUMO

As a PAC-1 derivative, SM-1 exhibts a promising antitumour property. To better understand the relationship between the drug concentrations and pharmacological effects, both liquid chromatography coupled with tandem mass spectrometry and high performance liquid chromatography methods were developed and validated in the work. Those methods were then applied to the pharmacokinetics (PK), tissue distribution and plasma protein binding (PPB) studies of SM-1. As a results, the proposed methods were demonstrated to be accurate, precise and stable for the analysis of the SM-1 in plasma and tissue samples. Meanwhile, the PK parameters of SM-1 showed that SM-1 had good PK properties. SM-1 had good absorption in the body, with 59.01% of the absolute bioavailability in rats and 55.63% of that in dogs. SM-1 rapidly distributed to all tissues, with the highest distribution in the lung and less in the brain and muscle. The PPB rates in rat plasma, dog plasma, and human plasma were 91.1%, 91.2%, and 90.7%, respectively. These good PK properties will contribute SM-1 to be a promising anti-tumour candidate. These results also provide insights into the further pharmacological investigation of SM-1.


Assuntos
Azepinas/farmacocinética , Proteínas Sanguíneas/metabolismo , Hidrazonas/farmacocinética , Absorção Fisico-Química , Animais , Azepinas/química , Disponibilidade Biológica , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Cães , Ensaios de Seleção de Medicamentos Antitumorais/instrumentação , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Hidrazonas/química , Pulmão/metabolismo , Masculino , Músculos/metabolismo , Piperazinas/química , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos , Distribuição Tecidual
7.
Eur J Med Chem ; 158: 428-441, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30241010

RESUMO

Aurora A, Aurora B and Kinase Insert Domain-containing Receptor (KDR) play essential roles in sustained cancer growth. In the present study, eighteen pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine derivatives were designed and synthesized. Most of the prepared compounds exhibited obviously enzymatic (Aurora A/B and KDR) activities. Among these analogs, compound 17g displayed significant Aurora A/B and KDR potencies with IC50 values of 46.2 nM, 37.6 nM and 21.6 nM, respectively. The results of further biological assays showed that compound 17g possessed moderate anti-proliferative activities against SNU-5, MKN-45 and MKN-74 cells lines, induced G2/M cell cycle arrest and apoptosis in MKN-45, MKN-74, SGC-7901 and SNU-5 cell lines, provided acceptable pharmacokinetic profiles (F = 63.8%), and inhibited the proliferation of SNU-5 tumors in vivo of mice. All of the above results suggested that pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine could be developed as a promising scaffold of multiple Aurora A/B and KDR inhibitors and 17g was worth of further research as a multi-targeted lead compound.


Assuntos
Aurora Quinase A/antagonistas & inibidores , Aurora Quinase B/antagonistas & inibidores , Azepinas/química , Azepinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Aurora Quinase A/metabolismo , Aurora Quinase B/metabolismo , Azepinas/farmacocinética , Azepinas/uso terapêutico , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/química , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
8.
Clin Cancer Res ; 24(24): 6142-6149, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30093449

RESUMO

PURPOSE: In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes. PATIENTS AND METHODS: We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts. RESULTS: Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median C max and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS. CONCLUSIONS: This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azepinas/administração & dosagem , Azepinas/farmacocinética , Criança , Pré-Escolar , Estudos de Coortes , Monitoramento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Lactente , Irinotecano/administração & dosagem , Irinotecano/farmacocinética , Imagem por Ressonância Magnética , Masculino , Recidiva Local de Neoplasia , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/mortalidade , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Retratamento , Temozolomida/administração & dosagem , Temozolomida/farmacocinética , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto Jovem
9.
Clin Cancer Res ; 24(24): 6150-6159, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30082475

RESUMO

PURPOSE: The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL. PATIENTS AND METHODS: Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 + 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 IHC was performed on available archival tissue. RESULTS: Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n = 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL). CONCLUSIONS: The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aurora Quinase A/antagonistas & inibidores , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azepinas/administração & dosagem , Azepinas/farmacocinética , Progressão da Doença , Monitoramento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/mortalidade , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Recidiva , Retratamento , Rituximab/administração & dosagem , Rituximab/farmacocinética , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/farmacocinética
10.
Mol Pharm ; 15(8): 3046-3059, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-29863884

RESUMO

The small GTPase RalA is a known mediator of anchorage-independent growth in cancers and is differentially regulated by adhesion and aurora kinase A (AURKA). Hence, inhibiting AURKA offers a means of specifically targeting RalA (over RalB) in cancer cells. MLN8237 (alisertib) is a known inhibitor of aurora kinases; its specificity for AURKA, however, is compromised by its poor solubility and transport across the cell membrane. A polymer nanovesicle platform is used for the first time to deliver and differentially inhibit AURKA in cancer cells. For this purpose, polysaccharide nanovesicles made from amphiphilic dextran were used as nanocarriers to successfully administer MLN8237 (VMLN) in cancer cells in 2D and 3D microenvironments. These nanovesicles (<200 nm) carry the drug in their intermembrane space with up to 85% of it released by the action of esterase enzyme(s). Lysotracker experiments reveal the polymer nanovesicles localize in the lysosomal compartment of the cell, where they are enzymatically targeted and MLN released in a controlled manner. Rhodamine B fluorophore trapped in the nanovesicles hydrophilic core (VMLN+RhB) allows us to visualize its uptake and localization in cells in a 2D and 3D microenvironment. In breast cancer, MCF-7 cells VMLN inhibits AURKA significantly better than the free drug at low concentrations (0.02-0.04 µM). This ensures that the drug in VMLN at these concentrations can specifically inhibit up to 94% of endogenous AURKA without affecting AURKB. This targeting of AURKA causes the downstream differential inhibition of active RalA (but not RalB). Free MLN8237 at similar concentrations and conditions failed to affect RalA activation. VMLN-mediated inhibition of RalA, in turn, disrupts the anchorage-independent growth of MCF-7 cells supporting a role for the AURKA-RalA crosstalk in mediating the same. These studies not only identify the polysaccharide nanovesicle to be an improved way to efficiently deliver low concentrations of MLN8237 to inhibit AURKA but, in doing so, also help reveal a role for AURKA and its crosstalk with RalA in anchorage-independent growth of MCF-7 cells.


Assuntos
Aurora Quinase A/antagonistas & inibidores , Azepinas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos/química , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Azepinas/farmacocinética , Neoplasias da Mama/patologia , Adesão Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Dextranos/química , Dextranos/farmacologia , Portadores de Fármacos/farmacologia , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Feminino , Humanos , Células MCF-7 , Nanopartículas/química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Solubilidade , Tensoativos/química , Tensoativos/farmacologia , Proteínas ral de Ligação ao GTP/metabolismo
12.
Clin Drug Investig ; 38(7): 631-638, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29705869

RESUMO

BACKGROUND AND OBJECTIVES: Suvorexant (MK-4305) is an orexin receptor antagonist approved for the treatment of insomnia in the USA and other regions. This randomized, double-blind, placebo-controlled, sequential-panel, Phase 1 trial assessed the safety, tolerability, and pharmacokinetic data following single and multiple dosing of suvorexant in healthy men (aged 18-45 years). METHODS: Within allocated panels, subjects (n = 8) were randomized to receive nightly doses of suvorexant (10, 20, 40, 80, and 100 mg) administered orally for 14 days, or placebo. Safety assessments included daily adverse event (AE) monitoring; pharmacokinetic data were obtained through periodic sampling. RESULTS: Of 40 subjects randomized, 39 completed the trial. The incidence of any AEs in the 10 and 20 mg groups was 67 and 83%, respectively, while 100% of subjects reported AEs in the dose groups of 40, 80, and 100 mg and the placebo group. The most frequently reported AEs were somnolence (n = 19 subjects), fatigue (n = 17), and headache (n = 15). Following single and multiple dosing, median time to reach maximum observed concentration ranged from 1.5 to 4.0 h and the apparent terminal half-life ranged from 7.7 to 14.5 h. Across the investigated doses, accumulation ratios for the area under the concentration-time curve and the maximum observed concentration were independent of dose and ranged from 1.21 to 1.60 and 1.00 to 1.46, respectively. CONCLUSIONS: Suvorexant was generally well tolerated after single and multiple dosing for 14 days. The findings support the once-nightly dosing regimen.


Assuntos
Azepinas/administração & dosagem , Azepinas/farmacocinética , Antagonistas dos Receptores de Orexina/administração & dosagem , Antagonistas dos Receptores de Orexina/farmacologia , Medicamentos Indutores do Sono/administração & dosagem , Medicamentos Indutores do Sono/farmacocinética , Triazóis/administração & dosagem , Triazóis/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Azepinas/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Fadiga/induzido quimicamente , Cefaleia/induzido quimicamente , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/efeitos adversos , Medicamentos Indutores do Sono/efeitos adversos , Triazóis/efeitos adversos , Adulto Jovem
13.
J Anal Toxicol ; 42(4): 276-283, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29300899

RESUMO

Suvorexant (Belsomra®) is a relatively new insomnia medication that has been available in USA and Japan since 2014. It is a dual orexin receptor antagonist that promotes sleep by inhibiting the binding of orexin neurons to the OX1R and OX2R receptors. In this report, we describe the detection and quantitation of suvorexant from the postmortem specimens of three separate autopsy cases handled by our department. Suvorexant was identified by fast gas chromatography/mass spectrometry during routine screening, and quantitated by a fully validated liquid chromatography-tandem mass spectroscopy method. Quantitation was achieved by positive electrospray ionization in the selected reaction monitoring mode. Monitored transitions were m/z 451 > 186 for quantitation and m/z 451 > 104 for qualification. To our knowledge, this is the first instance of suvorexant being quantitated from actual autopsy cases. It is likely that this compound will be encountered more often by the forensic toxicology community going forward.


Assuntos
Azepinas/farmacocinética , Toxicologia Forense , Triazóis/farmacocinética , Adulto , Idoso de 80 Anos ou mais , Autopsia , Azepinas/análise , Cromatografia Líquida , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem , Distribuição Tecidual , Triazóis/análise
14.
Expert Opin Investig Drugs ; 27(1): 105-112, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29260599

RESUMO

INTRODUCTION: Aurora kinases are essential mediators in cell mitosis. Amplification of these kinases can lead to the development of malignancy and may be associated with inferior survival. Alisertib is an oral aurora kinase inhibitor which has been shown to induce cell-cycle arrest and apoptosis in preclinical studies. It is currently under investigation for a wide variety of malignancies including hematologic (specifically Non-Hodgkin's lymphoma) and solid tumors. Areas covered: A PubMed search was performed to identify clinical studies reporting outcomes with alisertib. Promising results are notable in patients with peripheral T cell lymphoma in particular, forming the basis for the first phase 3 randomized trial of alisertib. Although it did show encouraging response rates, it failed to demonstrate superiority over the comparator arm at an interim analysis, halting further enrollment. Expert opinion: Despite disappointing early results, alisertib remains under investigation in a number of cancer types both as monotherapy and in combination with traditional cytotoxic chemotherapy, with encouraging results. Most common toxicities in early trials include myelosuppression alopecia, mucositis and fatigue. The relatively manageable toxicity profile of alisertib along with ease of dosing may allow it to be combined with other oral agents or traditional chemotherapy across a wide variety of malignancy types.


Assuntos
Azepinas/administração & dosagem , Linfoma não Hodgkin/tratamento farmacológico , Neoplasias/tratamento farmacológico , Pirimidinas/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Aurora Quinase A/antagonistas & inibidores , Azepinas/efeitos adversos , Azepinas/farmacocinética , Humanos , Linfoma não Hodgkin/patologia , Neoplasias/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
Br J Clin Pharmacol ; 84(1): 35-51, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28891222

RESUMO

AIMS: This population pharmacokinetic analysis was conducted to describe quantitatively the regional differences and sources of interpatient variability on the apparent oral clearance of alisertib. METHODS: A population pharmacokinetic analysis was performed on data from 671 cancer patients in Western countries and in Japan/East Asia to whom alisertib 5-150 mg once or twice daily (b.i.d.) was administered in multiple dosing schedules. The final model was used to simulate alisertib pharmacokinetics in patients in the West and East Asian regions in the single-agent schedule of 7 days of dosing in a 21-day cycle. Exposure-safety relationships for mechanism-related antiproliferative toxicities (neutropenia, mucositis and diarrhoea) were estimated by logistic regression. RESULTS: Alisertib pharmacokinetics were described by a two-compartment model with four-transit compartment absorption and linear elimination. The final model included a covariate effect of region on relative bioavailability, with patients in the East Asian region estimated to have a 52% higher bioavailability compared with Western patients. Population simulated exposure at 30 mg b.i.d. in patients in Asia was similar to that at 50 mg b.i.d. in Western patients [geometric mean (coefficient of variation) steady state area under the concentration-time curve over the dosing interval (AUC(0-τ) ): 21.4 µM.h (52.3%) and 24.1 µM.h (53.6%), respectively]. Exposure-AE relationships could be described for neutropenia, stomatitis and diarrhoea, supporting the lower dosage of alisertib in Asia for global clinical development. CONCLUSIONS: Model-based simulations support the achievement of similar alisertib exposures in patients in Asia who are administered a 40% lower dose compared with the Western population, thereby providing a quantitative clinical pharmacology bridging and regional dosing rationale for global drug development.


Assuntos
Antineoplásicos/farmacocinética , Aurora Quinase A/antagonistas & inibidores , Azepinas/farmacocinética , Relação Dose-Resposta a Droga , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Grupo com Ancestrais do Continente Asiático , Azepinas/administração & dosagem , Disponibilidade Biológica , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Esquema de Medicação , Feminino , Humanos , Incidência , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Estomatite/induzido quimicamente , Estomatite/epidemiologia , Adulto Jovem
16.
Invest New Drugs ; 36(2): 240-247, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28819760

RESUMO

Aims A primary objective of this study was to investigate the effect of single and multiple doses of alisertib, an investigational Aurora A kinase inhibitor, on the QTc interval in patients with advanced malignancies. The dose regimen used was the maximum tolerated dose which was also the recommended phase 3 dose (50 mg twice daily [BID] for 7 days in 21-day cycles). Methods Patients received a single dose of alisertib (50 mg) on Day 1, and multiple doses of alisertib (50 mg BID) on Days 4 through to the morning of Day 10 of the first cycle of treatment. Triplicate ECGs were collected at intervals over 10 to 24 h via Holter recorders on Days -1 (baseline), 1 and 10. Changes from time-matched baseline values were calculated for various ECG parameters including QTc, heart rate, PR and QRS intervals. Alisertib pharmacokinetics were also assessed during the study, and an exposure-QTc analysis was conducted. Results Fifty patients were included in the QTc analysis. The upper bounds of the 95% confidence intervals for changes from time-matched baseline QTcF and QTcI values were <5 ms across all study days, time points and correction methods. Alisertib did not produce clinically relevant effects on heart rate, PR or QRS intervals. There was no evidence of a concentration-QTc effect relationship. Conclusions Alisertib does not cause QTc prolongation and can be concluded to not have any clinically relevant effects on cardiac repolarization or ECG parameters at the single agent maximum tolerated dose of 50 mg BID.


Assuntos
Aurora Quinase A/antagonistas & inibidores , Azepinas/uso terapêutico , Drogas em Investigação/uso terapêutico , Eletrocardiografia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Aurora Quinase A/metabolismo , Azepinas/sangue , Azepinas/farmacocinética , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Metaboloma , Neoplasias/patologia , Pirimidinas/sangue , Pirimidinas/farmacocinética
17.
Invest New Drugs ; 36(2): 248-258, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28852909

RESUMO

Aim Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of alisertib, an investigational Aurora A kinase inhibitor, in patients with advanced malignancies. Methods In Study 1, patients received single doses of alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily [QD]) or rifampin (600 mg QD). In Study 2, patients received single doses of alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD). Blood samples for alisertib and 2 major metabolites were collected up to 72 h (Study 1) and 96 h (Study 2) postdose. Area under the curve from time zero extrapolated to infinity (AUC0-inf) and maximum concentrations (Cmax) were calculated and compared using analysis of variance to estimate least squares (LS) mean ratios and 90% confidence intervals (CIs). Results The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of esomeprazole were 1.28 (1.07, 1.53) and 1.14 (0.97, 1.35), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of rifampin were 0.53 (0.41, 0.70) and 1.03 (0.84, 1.26), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of itraconazole were 1.39 (0.99, 1.95) and 0.98 (0.82, 1.19), respectively. Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving alisertib.


Assuntos
Aurora Quinase A/antagonistas & inibidores , Azepinas/farmacocinética , Drogas em Investigação/farmacocinética , Esomeprazol/uso terapêutico , Itraconazol/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacocinética , Rifampina/uso terapêutico , Área Sob a Curva , Azepinas/sangue , Azepinas/farmacologia , Azepinas/uso terapêutico , Relação Dose-Resposta a Droga , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Esomeprazol/farmacologia , Feminino , Humanos , Itraconazol/farmacologia , Masculino , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/sangue , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Rifampina/farmacologia
18.
Mol Pharm ; 14(10): 3436-3447, 2017 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-28880093

RESUMO

Transporters at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) play a pivotal role as gatekeepers for efflux or uptake of endogenous and exogenous molecules. The protein expression of a number of them has already been determined in the brains of rodents, nonhuman primates, and humans using quantitative targeted absolute proteomics (QTAP). The dog is an important animal model for drug discovery and development, especially for safety evaluations. The purpose of the present study was to clarify the relevance of the transporter protein expression for drug distribution in the dog brain and CSF. We used QTAP to examine the protein expression of 17 selected transporters and receptors at the dog BBB and BCSFB. For the first time, we directly linked the expression of two efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), to regional brain and CSF distribution using specific substrates. Two cocktails, each containing one P-gp substrate (quinidine or apafant) and one BCRP substrate (dantrolene or daidzein) were infused intravenously prior to collection of the brain. Transporter expression varied only slightly between the capillaries of different brain regions and did not result in region-specific distribution of the investigated substrates. There were, however, distinct differences between brain capillaries and choroid plexus. Largest differences were observed for BCRP and P-gp: both were highly expressed in brain capillaries, but no BCRP and only low amounts of P-gp were detected in the choroid plexus. Kp,uu,brain and Kp,uu,CSF of both P-gp substrates were indicative of drug efflux. Also, Kp,uu,brain for the BCRP substrates was low. In contrast, Kp,uu,CSF for both BCRP substrates was close to unity, resulting in Kp,uu,CSF/Kp,uu,brain ratios of 7 and 8, respectively. We conclude that the drug transporter expression profiles differ between the BBB and BCSFB in dogs, that there are species differences in the expression profiles, and that CSF is not a suitable surrogate for unbound brain concentrations of BCRP substrates in dogs.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Encéfalo/irrigação sanguínea , Capilares/metabolismo , Plexo Corióideo/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/sangue , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/líquido cefalorraquidiano , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/líquido cefalorraquidiano , Animais , Azepinas/farmacocinética , Transporte Biológico , Barreira Hematoencefálica , Encéfalo/metabolismo , Dantroleno/farmacocinética , Cães , Feminino , Perfilação da Expressão Gênica , Isoflavonas/farmacocinética , Masculino , Proteômica/métodos , Quinidina/farmacocinética , Distribuição Tecidual , Triazóis/farmacocinética
19.
J Nucl Med ; 58(12): 2004-2009, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28572487

RESUMO

The purpose of this study was to assess safety, biodistribution, and radiation dosimetry in humans for the highly selective σ-1 receptor PET agent 18F-6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one (18F-FTC-146). Methods: Ten healthy volunteers (5 women, 5 men; age ± SD, 34.3 ± 6.5 y) were recruited, and written informed consent was obtained from all participants. Series of whole-body PET/MRI examinations were acquired for up to 3 h after injection (357.2 ± 48.8 MBq). Blood samples were collected, and standard vital signs (heart rate, pulse oximetry, and body temperature) were monitored at regular intervals. Regions of interest were delineated, time-activity curves were calculated, and organ uptake and dosimetry were estimated. Results: All subjects tolerated the PET/MRI examination well, and no adverse reactions to 18F-FTC-146 were reported. High accumulation of 18F-FTC-146 was observed in σ-1 receptor-dense organs such as the pancreas and spleen, moderate uptake in the brain and myocardium, and low uptake in bone and muscle. High uptake was also observed in the kidneys and bladder, indicating renal tracer clearance. The effective dose of 18F-FTC-146 was 0.0259 ± 0.0034 mSv/MBq (range, 0.0215-0.0301 mSv/MBq). Conclusion: First-in-human studies with clinical-grade 18F-FTC-146 were successful. Injection of 18F-FTC-146 is safe, and absorbed doses are acceptable. The potential of 18F-FTC-146 as an imaging agent for a variety of neuroinflammatory diseases is currently under investigation.


Assuntos
Azepinas/farmacocinética , Benzotiazóis/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Adulto , Azepinas/efeitos adversos , Azepinas/síntese química , Benzotiazóis/efeitos adversos , Benzotiazóis/síntese química , Feminino , Voluntários Saudáveis , Humanos , Marcação por Isótopo , Imagem por Ressonância Magnética , Masculino , Imagem Multimodal , Radiometria , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/síntese química , Receptores sigma/efeitos dos fármacos , Receptores sigma/metabolismo , Distribuição Tecidual , Imagem Corporal Total
20.
Mol Imaging Biol ; 19(5): 779-786, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28280965

RESUMO

PURPOSE: Sigma-1 receptors (S1Rs) play an important role in many neurological disorders. Simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) with S1R radioligands may provide valuable information for diagnosing and guiding treatment for these diseases. Our previously reported S1R radioligand, [18F]FTC-146, demonstrated high affinity for the S1R (K i = 0.0025 nM) and excellent selectivity for the S1R over the sigma-2 receptor (S2Rs; K i = 364 nM) across several species (from mouse to non-human primate). Herein, we report the clinical-grade radiochemistry filed with exploratory Investigational New Drug (eIND) and first-in-human PET/MRI evaluation of [18F]FTC-146. PROCEDURES: [18F]FTC-146 is prepared via a direct [18F] fluoride nucleophilic radiolabeling reaction and formulated in 0.9 % NaCl containing no more than 10 % ethanol through sterile filtration. Quality control (QC) was performed based on USP 823 before doses were released for clinical use. The safety and whole body biodistribution of [18F]FTC-146 were evaluated using a simultaneous PET/MR scanner in two representative healthy human subjects. RESULTS: [18F]FTC-146 was synthesized with a radiochemical yield of 3.3 ± 0.7 % and specific radioactivity of 8.3 ± 3.3 Ci/µmol (n = 10, decay corrected to EOB). Both radiochemical and chemical purities were >95 %; the prepared doses were stable for 4 h at ambient temperature. All QC test results met specified clinical criteria. The in vivo PET/MRI investigations showed that [18F]FTC-146 rapidly crossed the blood brain barrier and accumulated in S1R-rich regions of the brain. There were also radioactivity distributed in the peripheral organs, i.e., the lungs, spleen, pancreas, and thyroid. Furthermore, insignificant uptake of [18F]FTC-146 was observed in cortical bone and muscle. CONCLUSION: A reliable and automated radiosynthesis for providing routine clinical-grade [18F]FTC-146 for human studies was established in a modified GE TRACERlab FXFN. PET/MRI demonstrated the initial tracer biodistribution in humans, and clinical studies investigating different S1R-related diseases are in progress.


Assuntos
Azepinas/química , Azepinas/síntese química , Benzotiazóis/química , Benzotiazóis/síntese química , Imagem por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Adulto , Azepinas/farmacocinética , Benzotiazóis/farmacocinética , Feminino , Humanos , Masculino , Distribuição Tecidual
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