RESUMO
Peptides, despite their therapeutic potential, face challenges with undesirable pharmacokinetic (PK) properties and biodistribution, including poor oral absorption and cellular uptake, and short plasma elimination half-lives. Lipidation of peptides is a common strategy to improve their physicochemical and PK properties, making them viable drug candidates. For example, the plasma half-life of peptides has been extended via conjugation to lipids that are proposed to promote binding to serum albumin and thus protect against rapid clearance. Recent work has shown that lipid conjugation to oligodeoxynucleotides, polymers and small molecule drugs results in association not only with albumin, but also with lipoproteins, resulting in half-life prolongation and transport from administration sites via the lymphatics. Enhancing delivery into the lymph increases the efficacy of vaccines and therapeutics with lymphatic targets such as immunotherapies. In this study, the plasma PK, lymphatic uptake, and bioavailability of the glucagon-like peptide-1 (GLP-1) receptor agonist peptides, liraglutide (lipidated) and exenatide (non-lipidated), were investigated following subcutaneous (SC) administration to rats. As expected, liraglutide displayed an apparent prolonged plasma half-life (9.1 versus 1 h), delayed peak plasma concentrations and lower bioavailability (â¼10 % versus â¼100 %) compared to exenatide after SC administration. The lymphatic uptake of both peptides was relatively low (<0.5 % of the dose) although lymph to plasma concentration ratios were greater than one for several early timepoints suggesting some direct uptake into lymph. The low lymphatic uptake may be due to the nature of the conjugated lipid (a single-chain C16 palmitic acid in liraglutide) but suggests that other peptides with similar lipid conjugations may also have relatively modest lymphatic uptake. If delivery to the lymph is desired, conjugation to more lipophilic moieties with higher albumin and/or lipoprotein binding efficiencies, such as diacylglycerols, may be appropriate.
Assuntos
Exenatida , Liraglutida , Peptídeos , Ratos Sprague-Dawley , Animais , Exenatida/farmacocinética , Exenatida/administração & dosagem , Exenatida/farmacologia , Liraglutida/farmacologia , Liraglutida/farmacocinética , Liraglutida/administração & dosagem , Ratos , Masculino , Peptídeos/farmacocinética , Peptídeos/administração & dosagem , Lipídeos/química , Meia-Vida , Peçonhas/farmacocinética , Peçonhas/administração & dosagem , Disponibilidade Biológica , Distribuição Tecidual , Injeções Subcutâneas , Linfa/metabolismo , Linfa/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeo 1 Semelhante ao Glucagon/farmacocinética , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Sistema Linfático/metabolismo , Sistema Linfático/efeitos dos fármacos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologiaRESUMO
In the current work, we aimed to prepare a liraglutide-loaded porous microsphere-gel composite system. By employing polyethylene glycol (PEG) as a porogenic agent and poly (lactic-co-glycolic acid) copolymer (PLGA) as a carrier, the liraglutide microspheres were prepared and dispersed in a temperature-sensitive gel made of poloxamer 407 (F-127) and poloxamer 188 (F-68), which served as the gel matrix, to construct the composite system. The porous microsphere-gel composite system demonstrated prolonged and steady drug release, with a reduction to 4.7% in the initial release within 1 d, according to data from in vitro release tests. The drug release from the porous microspheres decreased from 53% to 29% during the rapid release phase as the PEG concentration increased and the release rate slowed down. In vivo experiments in rats revealed that the composite system prolonged the release period by about 10 d. The pharmacokinetic parameter AUC0-1 was decreased by 24.78 ng/ml*h, the initial burst release was decreased, and the blood drug concentration fluctuation was lessened. The construction of a porous microsphere-gel composite matrix offers a novel approach to the systems with a sustained, long-lasting release that utilizes rational design.
Assuntos
Liberação Controlada de Fármacos , Géis , Liraglutida , Microesferas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos Sprague-Dawley , Animais , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Porosidade , Liraglutida/administração & dosagem , Liraglutida/farmacocinética , Ratos , Masculino , Portadores de Fármacos/química , Polietilenoglicóis/química , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/química , Ácido Láctico/química , Poloxâmero/química , Preparações de Ação Retardada , Ácido Poliglicólico/químicaRESUMO
BACKGROUND: Glucagon-like peptide-1 (GLP-1) is an endogenous incretin hormone. Liraglutide, a GLP-1 receptor agonist, can lower blood sugar by increasing insulin production and inhibiting the production of glucagon. This study researched the bioequivalence and safety of the test and reference drugs in healthy Chinese subjects. RESEARCH DESIGN AND METHODS: Subjects (N = 28) were randomly divided into group A and group B at a ratio of 1:1 for a two-cycle cross-over study. There was single dose per cycle with subcutaneous injection of the test and reference drugs, respectively. The washout was set at 14 days. Plasma drug concentrations were detected by specific liquid chromatography and tandem mass spectrometry (LC-MS/MS) assays. Statistical analysis of major pharmacokinetic (PK) parameters was conducted to assess drug bioequivalence. In addition, we evaluated the safety of the drugs throughout the trial. RESULTS: The geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ for the test and reference drugs were 107.11%, 106.56%, 106.09%, respectively. The 90% confidence intervals (CIs) were all within 80%-125%, meeting the bioequivalence standards. In addition, both had good safety in this study. CONCLUSION: The study shows that the two drugs had similar bioequivalence and safety. CLINICAL TRIAL REGISTRATION: DCTR: CTR20190914; ClinicalTrials.gov: NCT05029076.
Assuntos
População do Leste Asiático , Liraglutida , Humanos , Área Sob a Curva , China , Cromatografia Líquida , Estudos Cross-Over , Liraglutida/administração & dosagem , Liraglutida/efeitos adversos , Liraglutida/sangue , Liraglutida/farmacocinética , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Injeções Subcutâneas , Monitoramento de MedicamentosRESUMO
This study aimed to evaluate the pharmacokinetics (PKs), safety, and immunogenicity of the biosimilar (RD12014) compared to reference liraglutide (Victoza) in healthy Chinese male subjects, so as to provide the basis for the similarity evaluation of the two drugs. Eligible subjects were randomized 1:1 to two sequences (RD12014-Victoza or Victoza-RD12014). Subjects received a single 0.6 mg dose of Victoza or RD12014 by abdominal subcutaneous injection during the first period. After a 7-day washout period, subjects received the alternative drug during the second period. Blood samples were collected at predefined timepoints for PKs and immunogenicity assessment. The primary PK end points were maximum plasma concentration (Cmax ) and area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last ). PK bioequivalence was achieved, if the 90% confidence intervals (CIs) of the geometric mean ratio (GMR) of Cmax and AUC0-last were within the range of 80.00-125.00%. Safety was assessed throughout the study. The 90% CIs of the GMR of RD12014 to Victoza for Cmax and AUC0-last were completely within the range of 80.00-125.00%. Thirteen treatment-related adverse events (TRAEs) were reported in 11 subjects (22.4%) in the RD12014 group, compared to 12 TRAEs reported in 12 subjects (24.5%) in the Victoza group. The blood samples of 49 subjects were negative for anti-drug antibody and the neutralizing antibody was not further detected. This study demonstrated PK similarity of RD12014 to Victoza in healthy Chinese male subjects. Safety and immunogenicity profiles were comparable between the two groups.
Assuntos
Medicamentos Biossimilares , Liraglutida , Humanos , Masculino , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/farmacocinética , China , Voluntários Saudáveis , Liraglutida/efeitos adversos , Liraglutida/farmacocinética , Equivalência TerapêuticaRESUMO
Oral drug delivery to treat diabetes is being increasingly researched. The mucus and the epithelial cell layers hinder drug delivery. We designed a self-ablating nanoparticle to achieve smart oral delivery to overcome the gastrointestinal barrier. We used the zwitterionic dilauroyl phosphatidylcholine, which exhibits a high affinity toward Oligopeptide transporter 1, to modify poly(lactic-co-glycolic acid) nanoparticles and load hemagglutinin-2 peptide to facilitate its escape from lysosomes. Nanoparticles exhibit a core-shell structure, the lipid layer is degraded by the lysosomes when the nanoparticles are captured by lysosomes, then the inner core of the nanoparticles gets exposed. The results revealed that the self-ablating nanoparticles exhibited higher encapsulation ability than the self-assembled nanoparticles (77% vs 64%) and with better stability. Quantitative cellular uptake, cellular uptake mechanisms, and trans-monolayer cellular were studied, and the results revealed that the cellular uptake achieved using the self-ablating nanoparticles was higher than self-assembling nanoparticles, and the number of uptake pathways via which the self-ablating nanoparticles functioned were higher than the self-assembling nanoparticles. Intestinal mucus permeation, in vivo intestinal circulation, was studied, and the results revealed that the small self-assembling nanoparticles exhibit a good extent of intestinal uptake in the presence of mucus. In vitro flip-flop, intestinal circulation revealed that the uptake of the self-ablating nanoparticles was 1.20 times higher than the self-assembled nanoparticles. Pharmacokinetic study and the pharmacodynamic study showed that the bioavailability and hypoglycemic effect of self-ablating nanoparticles were better than self-assembled nanoparticles.
Assuntos
Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Sistemas de Liberação de Fármacos por Nanopartículas/química , Animais , Transporte Biológico , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Absorção Intestinal/efeitos dos fármacos , Absorção Intestinal/fisiologia , Lipídeos/química , Liraglutida/administração & dosagem , Liraglutida/farmacocinética , Muco/efeitos dos fármacos , Tamanho da Partícula , Fosfatidilcolinas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Propriedades de SuperfícieRESUMO
Prediction of human pharmacokinetics (PK) from data obtained in animal studies is essential in drug development. Here, we present a thorough examination of how to achieve good pharmacokinetic data from the pig model for translational purposes by using single-species allometric scaling for selected therapeutic proteins: liraglutide, insulin aspart and insulin detemir. The predictions were based on non-compartmental analysis of intravenous and subcutaneous PK data obtained from two injection regions (neck, thigh) in two pig breeds, domestic pig and Göttingen Minipig, that were compared with PK parameters reported in humans. The effects of pig breed, injection site and injection depth (insulin aspart only) on the PK of these proteins were also assessed. Results show that the prediction error for human PK was within two-fold for most PK parameters in both pig breeds. Furthermore, pig breed significantly influenced the plasma half-life and mean absorption time (MAT), both being longer in Göttingen Minipigs compared to domestic pigs (P <0.01). In both breeds, thigh vs neck dosing was associated with a higher dose-normalized maximum plasma concentration and area under the curve as well as shorter MAT and plasma half-life (P <0.01). Finally, more superficial injections resulted in faster absorption, higher Cmax/dose and bioavailability of insulin aspart (P <0.05, 3.0 vs 5.0 mm injection depth). In conclusion, pig breed and injection region affected the PK of liraglutide, insulin aspart and insulin detemir and reliable predictions of human PK were demonstrated when applying single-species allometric scaling with the pig as a pre-clinical animal model.
Assuntos
Insulina Aspart/farmacocinética , Insulina Detemir/farmacocinética , Liraglutida/farmacocinética , Animais , Humanos , Injeções Intravenosas , Injeções Subcutâneas , Insulina Aspart/administração & dosagem , Insulina Detemir/administração & dosagem , Liraglutida/administração & dosagem , Sus scrofa , Suínos , Porco Miniatura , Pesquisa Translacional BiomédicaRESUMO
Objectives Based on the ellipse trial, liraglutide was recently approved for use in pediatric patients with type 2 diabetes. We report the comparative exposure of liraglutide in pediatric vs. adult patients. Methods In this pharmacokinetic (PK) and exposure-response meta-analysis, data from two pediatric trials (including ellipse) and two adult trials of liraglutide were compiled (1,137 PK observations from 116 patients) to determine the impact of body weight, age and sex on liraglutide exposure. The exposure-response relationship for glycated hemoglobin (HbA1c) and body weight was compared between pediatric and adult patients. Additionally, the relationships between exposure and change from baseline in body mass index (BMI) and BMI standard deviation score (SDS) were assessed. Results The same liraglutide dose showed comparable exposure levels in pediatric and adult patients. Body weight and sex were the most important covariates for liraglutide exposure. There was an increasing response with higher liraglutide concentrations, and greater reductions were observed from baseline in HbA1c at 26 weeks vs. placebo. A trend toward lower body weight, BMI and BMI SDS was observed at 26 weeks. Conclusions These results support use of the same liraglutide dosing regimen in children and adolescents, aged ≥10 years, as that used in adults.
Assuntos
Biomarcadores/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Liraglutida/farmacocinética , Liraglutida/uso terapêutico , Adolescente , Adulto , Glicemia/análise , Criança , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Método Duplo-Cego , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Humanos , Masculino , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Distribuição Tecidual , Adulto JovemRESUMO
A simple, fast and high-throughput LC-tandem mass spectrometry method was developed and validated to simultaneously measure liraglutide and insulin degludec in rat plasma. After protein precipitation, plasma samples were subjected to gradient elution using an InertSustain Bio C18 column with 1000/20/1 water/acetonitrile/formic acid (v/v/v) and 1000/1 acetonitrile/formic acid (v/v) as the mobile phase. The method was validated from 1.00 to 500 ng/mL of liraglutide and insulin degludec. Further, the extraction recovery from the plasma was 41.8%-49.2% for liraglutide and 56.5%-69.7% for insulin degludec. Intra- and inter-day precision of liraglutide was 3.5%-9.4% and 8.4%-9.8%, respectively, whereas its accuracy was between -12.6% and -1.3%. Intra- and inter-day precision of insulin degludec was 5.2%-13.6% and 11.8%-19.1%, respectively, showing an accuracy between -3.0% and 9.9%. As a result, the method was successfully applied to a pharmacokinetics study of liraglutide and insulin degludec following a single-dose subcutaneous administration to rats.
Assuntos
Cromatografia Líquida/métodos , Insulina de Ação Prolongada/sangue , Liraglutida/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Insulina de Ação Prolongada/química , Insulina de Ação Prolongada/farmacocinética , Limite de Detecção , Modelos Lineares , Liraglutida/química , Liraglutida/farmacocinética , Ratos , Reprodutibilidade dos TestesRESUMO
Until today, the oral delivery of peptide drugs is hampered due to their instability in the gastrointestinal tract and low mucosal penetration. To overcome these hurdles, PLA (polylactide acid)-nanoparticles were coated with a cyclic, polyarginine-rich, cell penetrating peptide (cyclic R9-CPP). These surface-modified nanoparticles showed a size and polydispersity index comparable to standard PLA-nanoparticles. The zeta potential showed a significant increase indicating successful CPP-coupling to the surface of the nanoparticles. Cryo-EM micrographs confirmed the appropriate size and morphology of the modified nanoparticles. A high encapsulation efficiency of liraglutide could be achieved. In vitro tests using Caco-2 cells showed high viability indicating the tolerability of this novel formulation. A strongly enhanced mucosal binding and penetration was demonstrated by a Caco-2 binding and uptake assay. In Wistar rats, the novel nanoparticles showed a substantial, 4.5-fold increase in the oral bioavailability of liraglutide revealing great potential for the oral delivery of peptide drugs.
Assuntos
Arginina/química , Peptídeos Penetradores de Células/química , Liraglutida/administração & dosagem , Liraglutida/efeitos adversos , Nanopartículas/química , Polímeros/química , Animais , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Feminino , Humanos , Imunoglobulina M , Liraglutida/farmacocinética , Ratos , Ratos Wistar , Técnicas de Síntese em Fase Sólida , SuínosRESUMO
Aim: An ultrasensitive UPLC-MS/MS assay for liraglutide was developed and validated according to US FDA and EMA guidelines and applied to the quantification of plasma concentrations after intravenous, nasal and oral administration of liraglutide to beagle dogs. Results: Liraglutide isolation was performed with a combined protein precipitation and solid-phase extraction protocol. The calibrated concentration range of 0.1-200 ng/ml was linear with correlation coefficients >0.998. Precise analysis was achieved through the utilization of an isotopically labeled internal standard. Absolute bioavailability of liraglutide after nasal and oral administration of liraglutide to beagle dogs was 0.03 and 0.006%, respectively. Conclusion: The assay matches the performance in sensitivity of the previously applied immunoassay and optimally covers the therapeutic range of liraglutide.
Assuntos
Análise Química do Sangue/métodos , Liraglutida/sangue , Liraglutida/farmacocinética , Administração Intranasal , Administração Oral , Animais , Disponibilidade Biológica , Precipitação Química , Cromatografia Líquida de Alta Pressão , Cães , Limite de Detecção , Liraglutida/administração & dosagem , Liraglutida/isolamento & purificação , Espectrometria de Massas em TandemRESUMO
BACKGROUND: Childhood obesity is a major public health concern with limited treatment options. OBJECTIVE: The aim of this study was to assess safety, tolerability, pharmacokinetics, and pharmacodynamics during short-term treatment with liraglutide in children (7-11 y) with obesity. METHODS: In this randomized, double-blind, placebo-controlled trial, 24 children received at least one dose of once-daily subcutaneous liraglutide (n = 16) or placebo (n = 8) starting at 0.3 mg with weekly dose escalations up to 3.0 mg or maximum tolerated dose, and 20 children completed the trial (14 in the liraglutide group and six in the placebo group). The primary endpoint was the number of adverse events. RESULTS: Baseline characteristics (mean ± standard deviation) included the following: age 9.9 ± 1.1 years, weight 71.5 ± 15.4 kg, and 62.5% male. Thirty-seven adverse events were reported in nine liraglutide-treated participants (56.3%) versus 12 events in five placebo-treated participants (62.5%). Most adverse events were mild in severity, three were of moderate severity, and none were severe. Gastrointestinal disorders were the most frequently reported events occurring in 37.5% of liraglutide-treated participants compared with placebo (12.5%). Six asymptomatic hypoglycaemic episodes occurred in five participants of whom four were liraglutide treated. Liraglutide exposure was consistent with dose proportionality. Body weight was the only covariate to significantly impact exposure. A significant reduction in body mass index (BMI) Z score from baseline to end of treatment (estimated treatment difference: -0.28; P = 0.0062) was observed. CONCLUSION: Short-term treatment with liraglutide in children with obesity revealed a safety and tolerability profile similar to trials in adults and adolescents with obesity, with no new safety issues.
Assuntos
Hipoglicemiantes/efeitos adversos , Liraglutida/efeitos adversos , Obesidade Infantil/tratamento farmacológico , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Criança , Método Duplo-Cego , Feminino , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Liraglutida/farmacocinética , Masculino , Resultado do TratamentoRESUMO
The plasma protein binding capability of drug substances represents an important assay parameter in drug discovery and development. For very strong plasma protein binding molecules, however, the free fraction in plasma fu is very small and therefore difficult to determine with standard methods. To solve this problem, the EScalate equilibrium shift in vitro assay was developed. Escalating concentrations of plasma were found to shift the binding equilibrium in solution between the test item and immobilized human serum albumin. Following liquid chromatography coupled to mass spectrometry analysis of the samples, the test compound's fu in plasma is calculated with a 2-dimensional fitting procedure. Comparability of EScalate assay results was demonstrated for 4 extensively studied small molecule drugs (carbamazepine, desipramine, pyrimethamine, and warfarin) as well as for liraglutide, a fatty acid-conjugated peptide drug with very strong plasma protein binding. The results were in good agreement with published data. A free fraction of 0.51% was determined for liraglutide. Our results confirm the compound's very strong plasma protein binding properties in a novel and robust assay system.
Assuntos
Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Liraglutida/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Liraglutida/sangue , Liraglutida/farmacocinética , Ligação Proteica , Reprodutibilidade dos Testes , Albumina Sérica Humana/metabolismo , Espectrometria de Massas em Tandem/métodosRESUMO
A simple, sensitive and selective LC-MS/MS method was developed for the quantitative analysis of liraglutide and validated in rat plasma. Human insulin was used as the internal standard. After a simple protein precipitation step, liraglutide was chromatographically separated using an InertSustain Bio C18 column with mobile phases comprising acetonitrile with 0.1% formic acid (A) and water with 0.1% formic acid (B). Detection was achieved using positive ion electrospray ionization in multiple-reaction monitoring (MRM) mode. Good linearity was observed in the concentration range 0.5-250â¯ng/mL (r2â¯>â¯0.99). The intra- and inter-day precision values (expressed as relative standard deviation, RSD) of liraglutide ranged from 1.97-7.63% and 5.25-11.9, respectively. The accuracy (expressed as relative error, RE) ranged from -8.79-11.4%. Both the recovery and matrix effect were within acceptable limits. This method was successfully applied for the pharmacokinetics study of liraglutide in rats after subcutaneous administration.
Assuntos
Cromatografia Líquida/métodos , Liraglutida/sangue , Liraglutida/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Feminino , Modelos Lineares , Liraglutida/química , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
AIM: An LC-MS/MS assay for the quantitation of liraglutide, a peptide-based injectable glucagon-like peptide-1 receptor agonist, has been developed as a convenient alternative to the enzyme-linked immunosorbent assay, and used to characterize liraglutide pharmacokinetics in cynomolgus monkeys. RESULTS: Assay calibration curves exhibited a linear dynamic range of 10-5000 ng/ml and correlation coefficient ≥0.98. Following a 30 µg/kg intravenous dose, liraglutide demonstrated low plasma clearance and distribution volume, which led to a terminal half-life of 6.59 h in monkeys. CONCLUSION: The dynamic range of our LC-MS/MS assay provides sufficient coverage of the average efficacious liraglutide concentrations in human plasma, and can be used for pharmacokinetics/pharmacodynamics studies in animals and potentially in humans.
Assuntos
Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Liraglutida/sangue , Liraglutida/farmacocinética , Técnicas Analíticas Microfluídicas , Administração Intravenosa , Animais , Cromatografia Líquida , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemiantes/administração & dosagem , Liraglutida/administração & dosagem , Macaca fascicularis , Masculino , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem , Terfenadina/administração & dosagem , Terfenadina/sangue , Terfenadina/farmacocinéticaRESUMO
Glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, exenatide, lixisenatide) have recently been used as anti-diabetes drugs. We examined relationships of the binding occupancy of GLP-1 receptors (Φ) and their clinical efficacy after administration of GLP-1 receptor agonists. Next, by focusing on changes of GLP-1 concentration after administration of dipeptidyl peptidase-4 (DPP-4) inhibitors (vildagliptin, alogliptin, sitagliptin, linagliptin), we analyzed the relationship between Φ and clinical efficacy. Furthermore, using Φ as a common parameter, we compared the clinical efficacy elicited by GLP-1 receptor agonists and DPP-4 inhibitors using a theoretical analysis method. The present results showed that GLP-1 receptor agonists produced their clinical effect at a relatively low level of Φ (1.1-10.7%) at a usual dose. Furthermore, it was suggested that the drugs might achieve their full effect at an extraordinarily low level of Φ. It was also revealed that the Φ value of DPP-4 inhibitors (0.83-1.3%) was at the lower end or lower than that of GLP-1 receptor agonists at a usual dose. Accordingly, the predicted value for hemoglobin A1c (HbA1c) reduction after administration of the GLP-1 receptor agonists was higher than that of DPP-4 inhibitors. We clarified the differences between the therapeutic effects associated with GLP-1 receptor agonists and DPP-4 inhibitors theoretically. Together, the present findings provide a useful methodology for proper usage of GLP-1 receptor agonists and DPP-4 inhibitors.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Modelos Moleculares , Adamantano/administração & dosagem , Adamantano/análogos & derivados , Adamantano/metabolismo , Adamantano/farmacocinética , Adamantano/uso terapêutico , Algoritmos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Exenatida , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacocinética , Ligantes , Liraglutida/administração & dosagem , Liraglutida/metabolismo , Liraglutida/farmacocinética , Liraglutida/uso terapêutico , Terapia de Alvo Molecular , Nitrilas/administração & dosagem , Nitrilas/metabolismo , Nitrilas/farmacocinética , Nitrilas/uso terapêutico , Peptídeos/administração & dosagem , Peptídeos/metabolismo , Peptídeos/farmacocinética , Peptídeos/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/metabolismo , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Pirrolidinas/administração & dosagem , Pirrolidinas/metabolismo , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapêutico , Reprodutibilidade dos Testes , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/metabolismo , Fosfato de Sitagliptina/farmacocinética , Fosfato de Sitagliptina/uso terapêutico , Uracila/administração & dosagem , Uracila/análogos & derivados , Uracila/metabolismoRESUMO
The long-acting glucagon-like peptide-1 analogue liraglutide has proven efficiency in the management of type 2 diabetes and also has beneficial effects on cardiovascular diseases. Liraglutide's protracted action highly depends on its capacity to bind to albumin via its palmitic acid part. However, in diabetes, albumin can undergo glycation, resulting in impaired drug binding. Our objective in this study was to assess the impact of human serum albumin (HSA) glycation on liraglutide affinity. Using fluorine labeling of the drug and 19F NMR, we determined HSA affinity for liraglutide in two glycated albumin models. We either glycated HSA in vitro by incubation with glucose (G25- or G100-HSA) or methylglyoxal (MGO-HSA) or purified in vivo glycated HSA from the plasma of diabetic patients with poor glycemic control. Nonglycated commercial HSA (G0-HSA) and HSA purified from plasma of healthy individuals served as controls. We found that glycation decreases affinity for liraglutide by 7-fold for G100-HSA and by 5-fold for MGO-HSA compared with G0-HSA. A similarly reduced affinity was observed for HSA purified from diabetic individuals compared with HSA from healthy individuals. Our results reveal that glycation significantly impairs HSA affinity to liraglutide and confirm that glycation contributes to liraglutide's variable therapeutic efficiency, depending on diabetes stage. Because diabetes is a progressive disease, the effect of glycated albumin on liraglutide affinity found here is important to consider when diabetes is managed with this drug.
Assuntos
Peptídeo 1 Semelhante ao Glucagon , Liraglutida/química , Albumina Sérica Humana/química , Diabetes Mellitus/sangue , Glicosilação , Humanos , Liraglutida/farmacocinética , Ressonância Magnética Nuclear Biomolecular , Ligação Proteica , Albumina Sérica Humana/metabolismoRESUMO
OBJECTIVES: To investigate the safety, tolerability, and pharmacokinetics of liraglutide in adolescents with obesity. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled trial. Twenty-one subjects, aged 12-17 years and Tanner stage 2-5, with obesity (body mass index [BMI] corresponding to both a BMI ≥95th percentile for age and sex and to a BMI of ≥30 kg/m2 for adults; additionally, BMI was ≤45 kg/m2) were randomized (2:1) to receive 5 weeks of treatment with liraglutide (0.6 mg with weekly dose increase to a maximum of 3.0 mg for the last week) (n = 14) or placebo (n = 7). The primary endpoint was number of treatment-emergent adverse events (TEAEs). Secondary endpoints included safety measures, and pharmacokinetic and pharmacodynamic endpoints. RESULTS: All participants receiving liraglutide, and 4 receiving placebo (57.1%), had at least 1 TEAE. The most common TEAEs were gastrointestinal disorders. No severe TEAEs, TEAE-related withdrawals, or deaths occurred. Twelve hypoglycemic episodes occurred in 8 participants receiving liraglutide and 2 in 1 participant receiving placebo. No severe hypoglycemic episodes were reported. Liraglutide exposure in terms of trough concentration increased with dose, although dose proportionality was confounded by unexpectedly low trough concentration values at the 2.4 mg dose. Exposure in terms of model-derived area under the plasma concentration time curve from 0 to 24 hours after dose in steady state was similar to that in adults with obesity. CONCLUSIONS: Liraglutide had a similar safety and tolerability profile compared with adults when administered to adolescents with obesity, with no unexpected safety/tolerability issues. Results suggest that the dosing regimen approved for weight management in adults may be appropriate for use in adolescents. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01789086.
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Hipoglicemia/induzido quimicamente , Liraglutida/farmacocinética , Liraglutida/uso terapêutico , Obesidade Infantil/tratamento farmacológico , Adolescente , Área Sob a Curva , Índice de Massa Corporal , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Hipoglicemia/epidemiologia , Injeções Subcutâneas , Liraglutida/efeitos adversos , Masculino , Dose Máxima Tolerável , Segurança do Paciente , Obesidade Infantil/diagnóstico , Valores de Referência , Medição de Risco , Resultado do TratamentoRESUMO
Bioresorbable electrospun fibres have highly functional features that can preserve drug efficacy, avoiding premature degradation, and control drug release rates over long periods. In parallel, it is known that Alzheimer's disease (AD) has been linked to impaired insulin signalling in the brain. Glucagon-like peptide 1 (GLP-1) analogues have beneficial effects on insulin release and possess exceptional neuroprotective properties. Herein, we describe for the first time the incorporation of a GLP-1 analogue, liraglutide, into electrospun poly (lactic acid) (PLA) fibres with in situ gelatin capsules, in order to provide the controlled release of liraglutide, improving neuroprotective properties. In this study, PLA, a bioresorbable polymer in which degradation products have neurogenesis characteristics, was electrospun and loaded with liraglutide. Moreover, PLA/liraglutide fibres were encapsulated with gelatin and were shown to have better properties than the non-encapsulated fibres in terms of the controlled release of liraglutide, which was accomplished in the present study for up to 60 days. We observed that this biodevice was completely encapsulated with gelatin, which made the material more hydrophilic than PLA fibres alone and the biodevice was able to enhance fibroblast interaction and reduce mitochondrial stress in a neuroblastoma cell line. In this manner, this study introduces a new material which can improve neuroprotective properties from AD oxidative stress via the sustained long-lasting release of liraglutide. Graphical Abstract á .
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Implantes Absorvíveis , Doença de Alzheimer/metabolismo , Citoproteção/fisiologia , Liraglutida/administração & dosagem , Estresse Oxidativo/fisiologia , Poliésteres/administração & dosagem , Implantes Absorvíveis/tendências , Doença de Alzheimer/prevenção & controle , Animais , Linhagem Celular Tumoral , Citoproteção/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Liraglutida/farmacocinética , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Poliésteres/farmacocinéticaRESUMO
In treatment of diabetes, it is much desired in clinics and challenging in pharmaceutics and material science to set up a long-acting drug delivery system. This study was aimed at constructing a new delivery system using thermogelling PEG/polyester copolymers. Liraglutide, a fatty acid-modified antidiabetic polypeptide, was selected as the model drug. The thermogelling polymers were presented by poly(ε-caprolactone-co-glycolic acid)-poly(ethylene glycol)-poly(ε-caprolactone-co-glycolic acid) (PCGA-PEG-PCGA) and poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA). Both the copolymers were soluble in water, and their concentrated solutions underwent temperature-induced sol-gel transitions. The drug-loaded polymer solutions were injectable at room temperature and gelled in situ at body temperature. Particularly, the liraglutide-loaded PCGA-PEG-PCGA thermogel formulation exhibited a sustained drug release manner over one week in both in vitro and in vivo tests. This feature was attributed to the combined effects of an appropriate drug/polymer interaction and a high chain mobility of the carrier polymer, which facilitated the sustained diffusion of drug out of the thermogel. Finally, a single subcutaneous injection of this formulation showed a remarkably improved glucose tolerance of mice for one week. Hence, the present study not only developed a promising long-acting antidiabetic formulation, but also put forward a combined strategy for controlled delivery of polypeptide.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Liraglutida/administração & dosagem , Polímeros/administração & dosagem , Animais , Glicemia/metabolismo , Géis , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Liraglutida/farmacocinética , Liraglutida/uso terapêutico , Camundongos , Camundongos Endogâmicos ICRRESUMO
INTRODUCTION: Type 2 diabetes is a complex disease requiring individualized and often multi-faceted treatment plans. Balancing glycemic control with adverse medication side effects can be challenging. Combination therapy of basal insulin and GLP-1 receptor agonist therapy appears to provide a balance between glycemic efficacy, hypoglycemia and weight gain. AREAS COVERED: Available pharmacokinetic data, clinical trials and abstracts regarding fixed-ratio combination of insulin degludec and liraglutide were reviewed. Literature was searched from PubMed and available abstracts using the search term IDegLira up to June 2016. EXPERT OPINION: Fixed-ratio combination of insulin degludec and liraglutide is associated with sustained glucose-lowering effects as assessed by HbA1c reduction. Overall, hypoglycemia is reduced and weight loss is observed compared to basal insulin alone. There is no significant increase in gastrointestinal side-effects, including nausea compared to non-glucagon-like peptide-1 receptor agonists. Pen injector delivery and dose-step titration allow for individualized therapy intensification. Combined treatment for type 2 diabetes with degludec and liraglutide therapy provides complementary therapeutic efficacy in the treatment of individuals with type 2 diabetes.