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1.
Int J Mol Sci ; 22(21)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34769030

RESUMO

The proteasome is responsible for mediating intracellular protein degradation and regulating cellular function with impact on tumor and immune effector cell biology. The proteasome is found predominantly in two forms, the constitutive proteasome and the immunoproteasome. It has been validated as a therapeutic drug target through regulatory approval with 2 distinct chemical classes of small molecular inhibitors (boronic acid derivatives and peptide epoxyketones), including 3 compounds, bortezomib (VELCADE), carfilzomib (KYPROLIS), and ixazomib (NINLARO), for use in the treatment of the plasma cell neoplasm, multiple myeloma. Additionally, a selective inhibitor of immunoproteasome (KZR-616) is being developed for the treatment of autoimmune diseases. Here, we compare and contrast the pharmacokinetics (PK), pharmacodynamics (PD), and metabolism of these 2 classes of compounds in preclinical models and clinical studies. The distinct metabolism of peptide epoxyketones, which is primarily mediated by microsomal epoxide hydrolase, is highlighted and postulated as a favorable property for the development of this class of compound in chronic conditions.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/farmacocinética , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Humanos
2.
Pharmacol Res ; 167: 105537, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33684510

RESUMO

Preclinical and clinical investigation on proteasome as a druggable target in cancer has led to the development of proteasome inhibitors (PIs) with different pharmacodynamic and pharmacokinetic properties. For example, carfilzomib has a better safety profile and a lower risk of clinically relevant drug-drug interactions than bortezomib, whereas ixazomib can be orally administered on a weekly basis due to a very long elimination half-life and high systemic exposure. The purpose of this review article is to elucidate the quantitative and qualitative differences in potency, selectivity, pharmacokinetics, safety and drug-drug interactions of clinically validated PIs to provide useful information for their clinical use in real life setting.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Proteassoma/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Compostos de Boro/efeitos adversos , Compostos de Boro/farmacocinética , Compostos de Boro/farmacologia , Compostos de Boro/uso terapêutico , Bortezomib/efeitos adversos , Bortezomib/farmacocinética , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Interações Medicamentosas , Glicina/efeitos adversos , Glicina/análogos & derivados , Glicina/farmacocinética , Glicina/farmacologia , Glicina/uso terapêutico , Humanos , Mieloma Múltiplo/tratamento farmacológico , Oligopeptídeos/efeitos adversos , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Inibidores de Proteassoma/efeitos adversos , Inibidores de Proteassoma/farmacocinética , Inibidores de Proteassoma/farmacologia
3.
J Microencapsul ; 38(3): 192-202, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33530812

RESUMO

AIM: Nano drug delivery systems can provide the opportunity to reduce side effects and improve the therapeutic aspect of a variety of drugs. Bortezomib (BTZ) is a proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma. Severe side effects of BTZ are the major dose-limiting factor. Particulate drug delivery systems for BTZ are polymeric and lipidic drug delivery systems. This review focussed on lipidic-nano drug delivery systems (LNDDSs) for the delivery of BTZ. RESULTS: LNDDSs including liposomes, solid lipid nanoparticles, and self-nanoemulsifying drug delivery systems showed reduce systemic side effects, improved therapeutic efficacy, and increased intestinal absorption. Besides LNDDSs were used to target-delivery of BTZ to cancer. CONCLUSION: Overall, LNDDSs can be considered as a novel delivery system for BTZ to resolve the treatment-associated restrictions.


Assuntos
Bortezomib/administração & dosagem , Sistemas de Liberação de Medicamentos , Lipídeos/química , Nanopartículas , Inibidores de Proteassoma/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Bortezomib/farmacocinética , Bortezomib/uso terapêutico , Composição de Medicamentos , Emulsões , Humanos , Lipossomos , Tamanho da Partícula , Inibidores de Proteassoma/farmacocinética , Inibidores de Proteassoma/uso terapêutico , Ratos
4.
Aging (Albany NY) ; 12(22): 22949-22974, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33203800

RESUMO

Proteasome inhibition demonstrates highly effective impact on multiple myeloma (MM) treatment. Here, we aimed to examine anti-tumor efficiency and underlying mechanisms of a novel well tolerated orally applicable proteasome inhibitor NNU546 and its hydrolyzed pharmacologically active form NNU219. NNU219 showed more selective inhibition to proteasome catalytic subunits and less off-target effect than bortezomib ex vivo. Moreover, intravenous and oral administration of either NNU219 or NNU546 led to more sustained pharmacodynamic inhibitions of proteasome activities compared with bortezomib. Importantly, NNU219 exhibited potential anti-MM activity in both MM cell lines and primary samples in vitro. The anti-MM activity of NNU219 was associated with induction of G2/M-phase arrest and apoptosis via activation of the caspase cascade and endoplasmic reticulum stress response. Significant growth-inhibitory effects of NNU219 and NNU546 were observed in 3 different human MM xenograft mouse models. Furthermore, such observation was even found in the presence of a bone marrow microenvironment. Taken together, these findings provided the basis for clinical trial of NNU546 to determine its potential as a candidate for MM treatment.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/administração & dosagem , Administração Intravenosa , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Disponibilidade Biológica , Bortezomib/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/patologia , Inibidores de Proteassoma/farmacocinética , Inibidores de Proteassoma/toxicidade , Ratos , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Anticancer Agents Med Chem ; 20(6): 643-650, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31985384

RESUMO

Cancer is a condition where there is an uncontrolled growth of cells resulting in high mortality. It is the second most frequent cause of death worldwide. Bortezomib (BTZ) is a Proteasome Inhibitor (PI) that is used for the treatment of a variety of cancers. It is the first PI that has received the approval of the US Food and Drug Administration (FDA) to treat mantle cell lymphoma and multiple myeloma. High incidence of sideeffects, limited dose, low water solubility, fast clearance, and drug resistance are the significant limitations of BTZ. Therefore, various drug delivery systems have been tried to overcome these limitations of BTZ in cancer therapy. Nanotechnology can potentially enhance the aqueous solubility of BTZ, increase its bioavailability, and control the release of BTZ at the site of administration. The lipid-based nanocarriers, such as liposomes, solid lipid NPs, and microemulsions, are some of the developments in nanotechnology, which could potentially enhance the therapeutic benefits of BTZ.


Assuntos
Antineoplásicos/administração & dosagem , Bortezomib/administração & dosagem , Portadores de Fármacos/química , Lipídeos/química , Nanopartículas/química , Inibidores de Proteassoma/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Bortezomib/farmacocinética , Bortezomib/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Humanos , Lipossomos/química , Nanotecnologia/métodos , Neoplasias/tratamento farmacológico , Inibidores de Proteassoma/farmacocinética , Inibidores de Proteassoma/farmacologia
6.
Clin Pharmacokinet ; 59(2): 207-216, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31313068

RESUMO

INTRODUCTION: The pharmacokinetics (PK) of the 20S proteasome inhibitor bortezomib are characterized by a large volume of distribution and a rapid decline in plasma concentrations within the first hour after administration. An increase in exposure was observed in the second week of treatment, which has previously been explained by extensive binding of bortezomib to proteasome in erythrocytes and peripheral tissues. We characterized the nonlinear population PK and pharmacodynamics (PD) of bortezomib in children with acute lymphoblastic leukemia. METHODS: Overall, 323 samples from 28 patients were available from a pediatric clinical study investigating bortezomib at an intravenous dose of 1.3 mg/m2 twice weekly (Dutch Trial Registry number 1881/ITCC021). A semi-physiological PK model for bortezomib was first developed; the PK were linked to the decrease in 20S proteasome activity in the final PK/PD model. RESULTS: The plasma PK data were adequately described using a two-compartment model with linear elimination. Increased concentrations were observed in week 2 compared with week 1, which was described using a Langmuir binding model. The decrease in 20S proteasome activity was best described by a direct effect model with a sigmoidal maximal inhibitory effect, representing the relationship between plasma concentrations and effect. The maximal inhibitory effect was 0.696 pmol AMC/s/mg protein (95% confidence interval 0.664-0.728) after administration. CONCLUSION: The semi-physiological model adequately described the nonlinear PK and PD of bortezomib in plasma. This model can be used to further optimize dosing of bortezomib.


Assuntos
Bortezomib/farmacocinética , Eritrócitos/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteassoma/farmacocinética , Administração Intravenosa , Adolescente , Bortezomib/administração & dosagem , Bortezomib/sangue , Bortezomib/uso terapêutico , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Eritrócitos/metabolismo , Estudos de Viabilidade , Feminino , Humanos , Lactente , Masculino , Modelos Biológicos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/sangue , Inibidores de Proteassoma/uso terapêutico , Recidiva
7.
Expert Opin Drug Metab Toxicol ; 15(6): 459-473, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31104525

RESUMO

Introduction: Multiple myeloma (MM) is the second most commonly diagnosed hematologic malignancy and has an increasing incidence and prevalence globally, and proteasome inhibitors (PIs) form the backbone of some of our most effective regimens for all phases of this disease in fit and frail patients. Areas covered: Strong understanding of the proteasome complex is increasingly important as the rapid development of new PIs and innovative myeloma therapies complicate the use of old and new combination regimens. We focus herein on the pharmacodynamics and pharmacokinetics of the approved PIs and others in development, including their safety and efficacy in corresponding clinical studies. Expert opinion: Advancements such as the first oral PI, ixazomib, with a more convenient route of administration and improved toxicity profile led to an improved quality of life, patient compliance, and all-oral combination regimens which are efficacious for long-term management of standard and high-risk MM. Novel pan-PIs, such as marizomib, hold the promise of superior clinical activity due to irreversible targeting of all multicatalytic proteinase complex subunits. Development of clinically validated biomarkers of PI sensitivity/resistance is required to inform utilization of the most optimal and effective, rationally targeted PI treatments for all MM patients.


Assuntos
Antineoplásicos/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Adesão à Medicação , Mieloma Múltiplo/patologia , Inibidores de Proteassoma/farmacocinética , Inibidores de Proteassoma/farmacologia , Qualidade de Vida
8.
Clin Pharmacol Ther ; 105(2): 376-387, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29446068

RESUMO

Model-informed drug development (MIDD) was central to the development of the oral proteasome inhibitor ixazomib, facilitating internal decisions (switch from body surface area (BSA)-based to fixed dosing, inclusive phase III trials, portfolio prioritization of ixazomib-based combinations, phase III dose for maintenance treatment), regulatory review (model-informed QT analysis, benefit-risk of 4 mg dose), and product labeling (absolute bioavailability and intrinsic/extrinsic factors). This review discusses the impact of MIDD in enabling patient-centric therapeutic optimization during the development of ixazomib.


Assuntos
Compostos de Boro/uso terapêutico , Glicina/análogos & derivados , Inibidores de Proteassoma/uso terapêutico , Animais , Disponibilidade Biológica , Compostos de Boro/farmacocinética , Compostos de Boro/farmacologia , Ensaios Clínicos Fase III como Assunto , Desenvolvimento de Medicamentos , Glicina/farmacocinética , Glicina/farmacologia , Glicina/uso terapêutico , Humanos , Modelos Teóricos , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/farmacocinética , Inibidores de Proteassoma/farmacologia
9.
Clin Pharmacokinet ; 58(2): 157-168, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29802543

RESUMO

Proteasome inhibitors disrupt multiple pathways in cells and the bone marrow microenvironment, resulting in apoptosis and inhibition of cell-cycle progression, angiogenesis, and proliferation. Bortezomib is a first-in-class proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma after one prior therapy. It is also effective in other plasma cell disorders and non-Hodgkin lymphomas. The main mechanism of action of bortezomib is to inhibit the chymotrypsin-like site of the 20S proteolytic core within the 26S proteasome, thereby inducing cell-cycle arrest and apoptosis. The pharmacokinetic profile of intravenous bortezomib is characterized by a two-compartment model with a rapid initial distribution phase followed by a longer elimination phase and a large volume of distribution. Bortezomib is available for subcutaneous and intravenous administration. Pharmacokinetic studies comparing subcutaneous and intravenous bortezomib demonstrated that systemic exposure was equivalent for both routes; pharmacodynamic parameters of 20S proteasome inhibition were also similar. Renal impairment does not influence the intrinsic pharmacokinetics of bortezomib. However, moderate or severe hepatic impairment causes an increase in plasma concentrations of bortezomib. Therefore, patients with moderate or severe hepatic impairment should start at a reduced dose. Because bortezomib undergoes extensive metabolism by hepatic cytochrome P450 3A4 and 2C19 enzymes, certain strong cytochrome P450 3A4 inducers and inhibitors can also alter the systemic exposure of bortezomib. This article critically reviews and summarizes the clinical pharmacokinetics and pharmacodynamics of bortezomib at various dosing levels and routes of administration as well as in specific patient subsets. In addition, we discuss the clinical efficacy and safety of bortezomib.


Assuntos
Antineoplásicos/administração & dosagem , Bortezomib/administração & dosagem , Neoplasias/metabolismo , Inibidores de Proteassoma/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Bortezomib/efeitos adversos , Bortezomib/farmacocinética , Humanos , Inibidores de Proteassoma/efeitos adversos , Inibidores de Proteassoma/farmacocinética
10.
Clin Pharmacokinet ; 58(4): 431-449, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30117017

RESUMO

Ixazomib, the first oral proteasome inhibitor, is approved in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. Ixazomib is a selective, potent, and reversible inhibitor of the 20S proteasome, and preferentially binds to and inhibits the ß5 chymotrypsin-like proteolytic site. Ixazomib absorption is rapid, with a median time to reach maximum plasma concentration of approximately 1 h post-dose. Ixazomib pharmacokinetics (PK) are adequately described by a three-compartment model (terminal half-life of 9.5 days) with first-order linear absorption (oral bioavailability of 58%). Plasma exposures of ixazomib increase in a dose-proportional manner. A high-fat meal decreases both the rate and extent of ixazomib absorption, supporting administration on an empty stomach. Population PK analyses demonstrated that no dose adjustment is required based on age, body size/weight, race, sex, mild-to-moderate renal impairment, or mild hepatic impairment. Results from dedicated studies indicate that a reduced starting dose (from 4 to 3 mg) is appropriate for patients with severe renal impairment, end-stage renal disease requiring dialysis, or moderate-to-severe hepatic impairment. Non-cytochrome P450 (CYP)-mediated metabolism appears to be the major clearance mechanism for ixazomib. Drug-drug interaction studies have shown no meaningful effects of strong inhibitors of CYP3A on ixazomib PK; however, the strong inducer rifampin caused a clinically relevant reduction in ixazomib exposure, supporting the recommendation to avoid concomitant administration of ixazomib with strong CYP3A inducers. Exposure-response analyses of data from the phase III TOURMALINE-MM1 registrational study demonstrate a favorable benefit-risk profile for the approved dose and regimen of weekly ixazomib 4 mg on days 1, 8, and 15 of each 28-day cycle.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Glicina/análogos & derivados , Inibidores de Proteassoma/farmacologia , Administração Oral , Antineoplásicos/química , Antineoplásicos/farmacocinética , Compostos de Boro/química , Compostos de Boro/farmacocinética , Relação Dose-Resposta a Droga , Glicina/química , Glicina/farmacocinética , Glicina/farmacologia , Humanos , Inibidores de Proteassoma/química , Inibidores de Proteassoma/farmacocinética
11.
Angiogenesis ; 22(1): 185-196, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30386953

RESUMO

Bone marrow microenvironment is known to support angiogenesis, thus contributing to progression of multiple myeloma (MM). Bortezomib, a proteasome inhibitor (PI) widely used in MM treatment, has anti-angiogenic activity. Extracellular vesicles (EVs), shedding from cell surface, serve as mediators in cell-to-cell communication. We have hypothesized that MM cells (MMCs) treated with bortezomib generate EVs that could diminish angiogenesis, thus limiting MM progression. In the present study, EVs were obtained from MMCs (RPMI-8226), untreated (naïve) or pre-treated with bortezomib. EVs were outlined using NanoSight, FACS, protein arrays and proteasome activity assays. The impact of MMC-EVs on endothelial cell (EC) functions was assessed, employing XTT assay, Boyden chamber and Western blot. A high apoptosis level (annexin V binding 70.25 ± 16.37%) was observed in MMCs following exposure to bortezomib. Compared to naïve EVs, a large proportion of bortezomib-induced EVs (Bi-EVs) were bigger in size (> 300 nm), with higher levels of annexin V binding (p = 0.0043).They also differed in content, presenting with increased levels of pro-inflammatory proteins, reduced levels of pro-angiogenic growth factors (VEGFA, PDGF-BB, angiogenin), and displayed lower proteasome activity. Naïve EVs were found to promote EC migration and proliferation via ERK1/2 and JNK1/2/3 phosphorylation, whereas Bi-EVs inhibited these functions. Moreover, Bi-EVs appeared to reduce EC proteasome activity. EVs released from apoptotic MMCs following treatment with bortezomib can promote angiogenesis suppression by decreasing proliferation and migration of EC. These activities are found to be mediated by specific signal transduction pathways.


Assuntos
Vesículas Extracelulares , Células Endoteliais da Veia Umbilical Humana/metabolismo , Mieloma Múltiplo/metabolismo , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteassoma , Bortezomib/farmacocinética , Bortezomib/farmacologia , Linhagem Celular Tumoral , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Vesículas Extracelulares/transplante , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Mieloma Múltiplo/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Inibidores de Proteassoma/farmacocinética , Inibidores de Proteassoma/farmacologia
12.
Br J Clin Pharmacol ; 85(3): 530-539, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30428505

RESUMO

AIMS: Oprozomib is an oral, second-generation, irreversible proteasome inhibitor currently in clinical development for haematologic malignancies, including multiple myeloma and other malignancies. Oprozomib is a rare example of a small molecule drug that demonstrates cytochrome P450 (CYP) mRNA suppression. This unusual property elicits uncertainty regarding the optimal approach for predicting its drug-drug interaction (DDI) risk. The current study aims to understand DDI potential during early clinical development of oprozomib. METHODS: To support early development of oprozomib (e.g. inclusion/exclusion criteria, combination study design), we used human hepatocyte data and physiologically-based pharmacokinetic (PBPK) modelling to predict its CYP3A4-mediated DDI potential. Subsequently, a clinical DDI study using midazolam as the substrate was conducted in patients with advanced malignancies. RESULTS: The clinical DDI study enrolled a total of 21 patients, 18 with advanced solid tumours. No patient discontinued oprozomib due to a treatment-related adverse event. The PBPK model prospectively predicted oprozomib 300 mg would not cause a clinically relevant change in exposure to CYP3A4 substrates (≤30%), which was confirmed by the results of this clinical DDI study. CONCLUSIONS: These results indicate oprozomib has a low potential to inhibit the metabolism of CYP3A4 substrates in humans. The study shows that cultured human hepatocytes are a more reliable system for DDI prediction than human liver microsomes for studying this class of compounds. Developing a PBPK model prior to a clinical DDI study has been valuable in supporting clinical development of oprozomib.


Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Neoplasias/tratamento farmacológico , Oligopeptídeos/farmacocinética , Inibidores de Proteassoma/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Desenvolvimento de Medicamentos , Interações Medicamentosas , Feminino , Hepatócitos , Humanos , Masculino , Microssomos Hepáticos , Midazolam/administração & dosagem , Midazolam/farmacocinética , Pessoa de Meia-Idade , Modelos Biológicos , Neoplasias/sangue , Neoplasias/patologia , Oligopeptídeos/administração & dosagem , Cultura Primária de Células , Inibidores de Proteassoma/administração & dosagem , Adulto Jovem
13.
J Med Chem ; 61(24): 11127-11143, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30380863

RESUMO

Selective immunoproteasome inhibition is a promising approach for treating autoimmune disorders, but optimal proteolytic active site subunit inhibition profiles remain unknown. We reveal here our design of peptide epoxyketone-based selective low molecular mass polypeptide-7 (LMP7) and multicatalytic endopeptidase complex subunit-1 (MECL-1) subunit inhibitors. Utilizing these and our previously disclosed low molecular mass polypeptide-2 (LMP2) inhibitor, we demonstrate a requirement of dual LMP7/LMP2 or LMP7/MECL-1 subunit inhibition profiles for potent cytokine expression inhibition and in vivo efficacy in an inflammatory disease model. These and additional findings toward optimized solubility led the design and selection of KZR-616 disclosed here and presently in clinical trials for treatment of rheumatic disease.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite Reumatoide/tratamento farmacológico , Morfolinas/farmacologia , Inibidores de Proteassoma/farmacologia , Administração Intravenosa , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Artrite Experimental/tratamento farmacológico , Linhagem Celular Tumoral , Cisteína Endopeptidases/metabolismo , Citocinas/metabolismo , Desenho de Fármacos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Morfolinas/química , Morfolinas/farmacocinética , Oligopeptídeos/farmacologia , Complexo de Endopeptidases do Proteassoma/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/química , Inibidores de Proteassoma/farmacocinética , Relação Estrutura-Atividade
14.
Nanoscale ; 10(38): 18387-18397, 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30256367

RESUMO

The treatment of metastatic tumors is highly desirable in clinics, which has also increased the interest in the design of nanoscale drug delivery systems. Bone metastasis is one of the most common pathways in the metastasis of breast cancer, and it is also an important cause for tumor recurrence and death. The aryl boronate group, as an acid-labile linker, has been introduced into nano-assemblies in recent years. Especially, as a proteasome inhibitor anticancer drug with a boric acid group, bortezomib can facilitate the formation of pH-sensitive aryl boric acid ester linkage with the catecholic group. In this study, bortezomib-loaded micelles with bone targeting properties were constructed for the treatment of breast cancer bone metastasis. The mixed micelles employed alendronate (ALN) as the bone-targeting ligand and encapsulated bortezomib-catechol conjugates as the cargo. In vitro and in vivo studies showed that compared with free drugs or control micelles, these prodrug micelles (ALN-NP) exhibited many favorable properties such as reduced systemic toxicity and improved therapeutic effects. Therefore, ALN-NP is promising as a nanovehicle for bone-targeting delivery of chemotherapeutic drugs. Furthermore, this study offers a novel strategy combining bone targeting and aryl boronate-based pH-responsive drug release for anti-metastasis therapy.


Assuntos
Alendronato/química , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Bortezomib/química , Catecóis/química , Sistemas de Liberação de Medicamentos , Micelas , Alendronato/farmacocinética , Alendronato/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Bortezomib/farmacocinética , Bortezomib/uso terapêutico , Neoplasias da Mama/patologia , Linhagem Celular , Modelos Animais de Doenças , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/uso terapêutico , Feminino , Hemólise/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Inibidores de Proteassoma/química , Inibidores de Proteassoma/farmacocinética , Inibidores de Proteassoma/uso terapêutico , Células RAW 264.7
15.
J Med Chem ; 61(20): 9177-9204, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30265557

RESUMO

Macrocyclization has been frequently utilized for optimizing peptide or peptidomimetic-based compounds. In an attempt to obtain potent, metabolically stable, and orally available proteasome inhibitors, 30 oprozomib-derived macrocyclic peptides with structural diversity in their N-terminus and linker were successively designed and synthesized for structure-activity relationship (SAR) studies. As a consequence, the macrocyclic peptides with N-methyl-pyrazole (24p, 24x), imidazole (24t), and pyrazole (24v) as their respective N-termini exhibited favorable in vitro activity and metabolic stability, which translated into their potent in vivo proteasome inhibitory activity after oral administration. In particular, compound 24v, as the most distinguished one among this series, displayed excellent chymotrypsin-like (ChT-L, ß5) inhibitory potency (IC50 = 16 nM), low nanomolar antiproliferative activity against all three of the tested cell lines, and superior metabolic stability in mouse liver microsome (MLM), as well as favorable inhibition against ChT-L compared to that of oprozomib in BABL/c mice following po administration at a comparatively low dose, thereby representing a promising candidate for further development.


Assuntos
Cetonas/química , Compostos Macrocíclicos/química , Peptídeos/química , Peptídeos/farmacologia , Inibidores de Proteassoma/química , Inibidores de Proteassoma/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Humanos , Camundongos , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Permeabilidade , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/farmacocinética , Conformação Proteica , Distribuição Tecidual
16.
Arch Biochem Biophys ; 639: 52-58, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29305052

RESUMO

Bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib are anticancer drugs that target the proteasomal system. Carfilzomib and oprozomib are epoxyketones that form an irreversible covalent bond with the 20S proteasome, whereas bortezomib, ixazomib, and delanzomib are boronic acids that form slowly reversible adducts. The binding kinetics of some of these drugs have either not been well characterized, or have been studied under a variety of different conditions. Utilizing a fluorogenic substrate the kinetics of the slow-binding inhibition of the chymotrypsin-like proteasomal activity of human 20S proteasome was determined under a standard set of conditions in order to compare the kinetic and equilibrium properties of these drugs. Progress curve analysis was used to obtain second order "on" and first-order "off" rate constants, and equilibrium- and kinetically-determined inhibitor dissociation constants. Oprozomib inhibited the 20S proteasome with a second-order binding "on" rate constant that was 60-fold slower than for ixazomib, the fastest binding drug. Delanzomib dissociated from its complex with the 20S proteasome with a half-time that was more than 20-fold slower than for ixazomib, the fastest dissociating drug. The differences in the binding and the dissociation of these drugs may, in part, explain some of their pharmacological and toxicological properties.


Assuntos
Antineoplásicos/química , Modelos Químicos , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/química , Antineoplásicos/farmacocinética , Humanos , Cinética , Inibidores de Proteassoma/farmacocinética , Ligação Proteica
17.
Invest New Drugs ; 36(3): 407-415, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28932928

RESUMO

This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1 mg oral solution dose of [14C]-ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled ixazomib (4 mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to assess the mass balance (by accelerator mass spectrometry), excretion, and PK of ixazomib. During Part B of the study, patients received non-radiolabeled ixazomib (4 mg capsules) on days 1, 8, and 15 of 28-day cycles. After oral administration, ixazomib was rapidly absorbed with a median plasma Tmax of 0.5 h and represented 70% of total drug-related material in plasma. The mean total recovery of administered TRA was 83.9%; 62.1% in urine and 21.8% in feces. Only 3.23% of the administered dose was recovered in urine as unchanged drug up to 168 h post dose, suggesting that most of the TRA in urine was attributable to metabolites. All patients experienced a treatment-emergent adverse event, which most commonly involved the gastrointestinal system. These findings suggest that ixazomib is extensively metabolized, with urine representing the predominant route of excretion of drug-related material.Trial ID: ClinicalTrials.gov # NCT01953783.


Assuntos
Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Radioisótopos de Carbono/farmacocinética , Glicina/análogos & derivados , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Proteassoma/farmacocinética , Inibidores de Proteassoma/uso terapêutico , Administração Oral , Idoso , Compostos de Boro/administração & dosagem , Compostos de Boro/sangue , Radioisótopos de Carbono/administração & dosagem , Radioisótopos de Carbono/sangue , Fezes , Feminino , Glicina/administração & dosagem , Glicina/sangue , Glicina/farmacocinética , Glicina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/sangue , Radioatividade , Resultado do Tratamento , Urina
18.
J Clin Pharmacol ; 58(2): 180-192, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28800141

RESUMO

At clinically relevant ixazomib concentrations, in vitro studies demonstrated that no specific cytochrome P450 (CYP) enzyme predominantly contributes to ixazomib metabolism. However, at higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms, with the estimated relative contribution being highest for CYP3A at 42%. This multiarm phase 1 study (Clinicaltrials.gov identifier: NCT01454076) investigated the effect of the strong CYP3A inhibitors ketoconazole and clarithromycin and the strong CYP3A inducer rifampin on the pharmacokinetics of ixazomib. Eighty-eight patients were enrolled across the 3 drug-drug interaction studies; the ixazomib toxicity profile was consistent with previous studies. Ketoconazole and clarithromycin had no clinically meaningful effects on the pharmacokinetics of ixazomib. The geometric least-squares mean area under the plasma concentration-time curve from 0 to 264 hours postdose ratio (90%CI) with vs without ketoconazole coadministration was 1.09 (0.91-1.31) and was 1.11 (0.86-1.43) with vs without clarithromycin coadministration. Reduced plasma exposures of ixazomib were observed following coadministration with rifampin. Ixazomib area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration was reduced by 74% (geometric least-squares mean ratio of 0.26 [90%CI 0.18-0.37]), and maximum observed plasma concentration was reduced by 54% (geometric least-squares mean ratio of 0.46 [90%CI 0.29-0.73]) in the presence of rifampin. The clinical drug-drug interaction study results were reconciled well by a physiologically based pharmacokinetic model that incorporated a minor contribution of CYP3A to overall ixazomib clearance and quantitatively considered the strength of induction of CYP3A and intestinal P-glycoprotein by rifampin. On the basis of these study results, the ixazomib prescribing information recommends that patients should avoid concomitant administration of strong CYP3A inducers with ixazomib.


Assuntos
Antineoplásicos/farmacocinética , Compostos de Boro/farmacocinética , Indutores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Glicina/análogos & derivados , Inibidores de Proteassoma/farmacocinética , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Claritromicina/farmacologia , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Feminino , Glicina/farmacocinética , Humanos , Cetoconazol/farmacologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Neoplasias/metabolismo , Rifampina/farmacologia
19.
J Clin Pharmacol ; 58(1): 114-121, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28783865

RESUMO

The oral proteasome inhibitor ixazomib is approved in multiple countries in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. Two oral capsule formulations of ixazomib have been used during clinical development. This randomized, 2-period, 2-sequence crossover study (Clinicaltrials.gov identifier NCT01454076) assessed the relative bioavailability of capsule B in reference to capsule A in adult patients with advanced solid tumors or lymphoma. The study was conducted in 2 parts. In cycle 1 (pharmacokinetic cycle), patients received a 4-mg dose of ixazomib as capsule A or capsule B on day 1, followed by a 4-mg dose of the alternate capsule formulation on day 15. Pharmacokinetic samples were collected over 216 hours postdose. After the pharmacokinetic cycle, patients could continue in the study and receive ixazomib (capsule B only) on days 1, 8, and 15 of each 28-day cycle. Twenty patients were enrolled; of these, 14 were included in the pharmacokinetic-evaluable population. Systemic exposures of ixazomib were similar after administration of capsule A or capsule B. The geometric least-squares mean ratios (capsule B versus capsule A) were 1.16 for Cmax (90% confidence interval [CI], 0.84-1.61) and 1.04 for AUC0-216 (90%CI, 0.91-1.18). The most frequently reported grade 3 drug-related adverse events were fatigue (15%) and nausea (10%); there were no grade 4 drug-related adverse events. These results support the combined analysis of data from studies that used either formulation of ixazomib during development.


Assuntos
Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Cápsulas/farmacocinética , Cápsulas/uso terapêutico , Glicina/análogos & derivados , Linfoma/tratamento farmacológico , Inibidores de Proteassoma/farmacocinética , Administração Oral , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Compostos de Boro/efeitos adversos , Cápsulas/efeitos adversos , Química Farmacêutica/métodos , Estudos Cross-Over , Fadiga/induzido quimicamente , Feminino , Glicina/efeitos adversos , Glicina/farmacocinética , Glicina/uso terapêutico , Humanos , Linfoma/metabolismo , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Inibidores de Proteassoma/efeitos adversos , Inibidores de Proteassoma/uso terapêutico
20.
Invest New Drugs ; 36(4): 619-628, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29094232

RESUMO

Purpose This phase I study investigated bortezomib in solid tumors used as a daily subcutaneous regimen. Previous regimens showed only modest activity in solid tumors which was potentially related to sub-optimal tumor penetration. We aimed at exploring if daily low dose administration of bortezomib may allow a greater and tolerable pharmacokinetic exposure which might be required for antitumor activity in solid tumors. Patients and methods This 3 + 3 design, dose escalation, monocentric study aimed at defining the maximum tolerated dose of daily low dose schedule of bortezomib. Tolerability, pharmacokinetics, pharmacodynamics, antitumor activity, biomarkers for proteasome inhibition, pre- and post-treatment tumor biopsies were also evaluated. Results A total of eighteen patients were dosed in 3 bortezomib cohorts (0.5, 0.6 and 0.7 mg/m2), with 3, 11 and 4 patients respectively. Three patients experienced dose-limiting toxicities: Grade (G) 3 Sweet's syndrome (at 0.6 mg/m2), G3 asthenia and anorexia or ataxia (2 patients at 0.7 mg/m2). The most common study drug-related adverse events (all grades) were thrombocytopenia (72%), fatigue (56%), neuropathy (50%), anorexia (44%) and rash (39%). Dose 0.6 mg/m2 of bortezomib was considered as the recommended phase II dose. A significant tumor shrinkage (-36% according to WHO criteria) was observed in one patient with heavily pre-treated GIST, and 2 minor responses (-20%) were recorded in two patients with melanoma and mesothelioma. Conclusion This daily subcutaneous regimen of bortezomib showed a dose dependent plasma exposure, evidence of target inhibition and preliminary signs of clinical activity. However, cumulative neurological toxicity of this dose-dense daily regimen might preclude its further clinical development.


Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Produtos Biológicos/farmacocinética , Produtos Biológicos/uso terapêutico , Bortezomib/farmacocinética , Bortezomib/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Produtos Biológicos/efeitos adversos , Bortezomib/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteassoma/efeitos adversos , Inibidores de Proteassoma/farmacocinética , Inibidores de Proteassoma/uso terapêutico
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