RESUMO
Chronic kidney disease (CKD) is a complication of diabetes that affects circulating drug concentrations and elimination of drugs from the body. Multiple drugs may be prescribed for treatment of diabetes and co-morbidities, and CKD complicates the pharmacotherapy selection and dosing regimen. Characterizing variations in renal drug clearance using models requires large clinical datasets that are costly and time-consuming to collect. We propose a flexible approach to incorporate impaired renal clearance in pharmacokinetic (PK) models using descriptive statistics and secondary data with mechanistic models and PK first principles. Probability density functions were generated for various drug clearance mechanisms based on the degree of renal impairment and used to estimate the total clearance starting from glomerular filtration for metformin (MET) and dapagliflozin (DAPA). These estimates were integrated with PK models of MET and DAPA for simulations. MET renal clearance decreased proportionally with a reduction in estimated glomerular filtration rate (eGFR) and estimated net tubular transport rates. DAPA total clearance varied little with renal impairment and decreased proportionally to reported non-renal clearance rates. Net tubular transport rates were negative to partially account for low renal clearance compared with eGFR. The estimated clearance values and trends were consistent with MET and DAPA PK characteristics in the literature. Dose adjustment based on reduced clearance levels estimated correspondingly lower doses for MET and DAPA while maintaining desired dose exposure. Estimation of drug clearance rates using descriptive statistics and secondary data with mechanistic models and PK first principles improves modeling of CKD in diabetes and can guide treatment selection.
Assuntos
Compostos Benzidrílicos , Taxa de Filtração Glomerular , Glucosídeos , Hipoglicemiantes , Metformina , Modelos Biológicos , Insuficiência Renal Crônica , Compostos Benzidrílicos/farmacocinética , Compostos Benzidrílicos/administração & dosagem , Metformina/farmacocinética , Metformina/administração & dosagem , Glucosídeos/farmacocinética , Glucosídeos/administração & dosagem , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Simulação por Computador , MasculinoRESUMO
Getting the dose right is a key challenge in drug development; model-informed drug development (MIDD) provides powerful tools to shape dose strategies and inform decision making. In this tutorial, the case study of the ZENITH trials showcases how a set of clinical pharmacology and MIDD approaches informed an impactful dose strategy. The endothelin A receptor antagonist zibotentan, combined with the sodium-glucose co-transporter-2 inhibitor dapagliflozin, has yielded a robust and significant albuminuria reduction in the Phase IIb trial ZENITH-CKD and is being investigated for reduction of kidney function decline in a high-risk chronic kidney disease population in the Phase III trial ZENITH High Proteinuria. Endothelin antagonist treatment has, until now, been limited by the class effect fluid retention. ZENITH-CKD investigated a wide range of zibotentan doses based on pharmacokinetics in renal impairment, competitor-data exposure-response modeling, and clinical trial simulations. Recruitment delays reduced interim analysis data availability; here, supportive dose-response modeling recovered decision-making confidence. At trial completion, the low-dose arm enabled Phase III dose selection between Phase IIb doses. Dose-response modeling of efficacy and Kaplan-Meier analyses of tolerability identified a kidney-function-based low-dose strategy of 0.25 or 0.75 mg zibotentan (with 10 mg dapagliflozin) to balance benefit/risk in ZENITH High Proteinuria. The applied clinical pharmacology and MIDD principles enabled successful Phase IIb dose finding, rationalized and built confidence in the innovative Phase III dosing strategy and identified a potential therapeutic window for zibotentan/dapagliflozin, providing the opportunity for a significant improvement in the treatment of chronic kidney disease with high proteinuria.
Assuntos
Compostos Benzidrílicos , Desenvolvimento de Medicamentos , Glucosídeos , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Compostos Benzidrílicos/farmacocinética , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Desenvolvimento de Medicamentos/métodos , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Glucosídeos/administração & dosagem , Glucosídeos/farmacocinética , Glucosídeos/farmacologia , Relação Dose-Resposta a Droga , Ensaios Clínicos Fase II como Assunto , Insuficiência Renal Crônica/tratamento farmacológico , Antagonistas do Receptor de Endotelina A/administração & dosagem , Antagonistas do Receptor de Endotelina A/farmacocinética , Modelos Biológicos , Ensaios Clínicos Fase III como Assunto , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Combinação de Medicamentos , GlicosídeosRESUMO
The co-administration of dapagliflozin (DPF) and sacubitril/valsartan (LCZ696) has emerged as a promising therapeutic approach for managing heart failure. Given that DPF and LCZ696 are substrates for P-glycoprotein, there is a plausible potential for drug-drug interactions when administered concomitantly. To investigate the pharmacokinetic changes when these drugs are co-administered, we have established and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method capable of simultaneously detecting DPF, LBQ657 (the active metabolite of sacubitril) and valsartan in rat plasma. This method has demonstrated selectivity, sensitivity, and accuracy. Drug-drug interactions were examined by the LC-MS/MS method. The mechanisms were investigated using everted intestinal sac models and Caco-2 cells. The results showed that DPF significantly increased the area under the curve (AUC(0-t)) (3,563.3 ± 651.7 vs. 7,146.5 ± 1,714.9 h µg/L) of LBQ657 (the active metabolite of sacubitril) and the AUC(0-t) (24,022.4 ± 6,774.3 vs. 55,728.3 ± 32,446.3 h µg/L) of valsartan after oral co-administration. Dapagliflozin significantly increased the amount of LBQ657 and valsartan in intestinal sacs by 1- and 1.25-fold at 2.25 h. Caco-2 cell uptake studies confirmed that P-glycoprotein is the transporter involved in this interaction. This finding enhances the understanding of drug-drug interactions in the treatment of heart failure and provides a guidence for clinical therapy.
Assuntos
Aminobutiratos , Compostos Benzidrílicos , Compostos de Bifenilo , Glucosídeos , Tetrazóis , Valsartana , Animais , Humanos , Masculino , Ratos , Aminobutiratos/sangue , Aminobutiratos/farmacocinética , Compostos Benzidrílicos/sangue , Compostos Benzidrílicos/farmacocinética , Compostos de Bifenilo/sangue , Compostos de Bifenilo/farmacocinética , Células CACO-2 , Combinação de Medicamentos , Interações Medicamentosas , Glucosídeos/farmacocinética , Glucosídeos/sangue , Espectrometria de Massa com Cromatografia Líquida , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tetrazóis/sangue , Tetrazóis/farmacocinética , Valsartana/sangue , Valsartana/farmacocinética , FemininoRESUMO
INTRODUCTION: In adults, sodium-glucose cotransporter type 2 inhibitors have revolutionised the treatment of type 2 diabetes mellitus, heart failure, and chronic kidney disease. OBJECTIVE: We aimed to review information on compassionate use, clinical pharmacology, efficacy, and safety of dapagliflozin and empagliflozin in children. METHODS: We conducted a systematic review of published clinical trials, case reports, and observational studies in Medline, Excerpta Medica, and Web of Science databases from inception to September 2023. For the two randomised controlled trials on type 2 diabetes mellitus (T2DM), we implemented a meta-analysis on the primary outcome (mean difference in glycosylated haemoglobin [HbA1c] between intervention and placebo groups). Review Manager (RevMan), version 5.4.1, was used for this purpose. RESULTS: Thirty-five articles (nine case reports, ten case series, one prospective non-controlled trial, four controlled randomised trials, two surveys, six pharmacokinetic studies, and three pharmacovigilance studies) were selected, in which 415 children were exposed to either dapagliflozin or empagliflozin: 189 diabetic patients (mean age 14.7 ± 2.9 years), 32 children with glycogen storage disease type Ib (GSD Ib), glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency, or severe congenital neutropenia type 4 (8.5 ± 5.1 years), 47 children with kidney disease or heart failure (11.2 ± 6.1 years), 84 patients in pharmacokinetic studies (15.1 ± 2.3 years), and 63 patients in toxicological series. The effect of dapagliflozin and empagliflozin in T2DM was demonstrated by HbA1c reduction in two randomised trials among a total of 177 adolescents, with a mean HbA1c difference of -0.82% (95% confidence interval -1.34 to -0.29) as compared to placebo (no heterogeneity, I2 = 0%). Dosage ranged between 5 and 20 mg (mean 11.4 ± 3.7) once daily for dapagliflozin and between 5 and 25 mg (mean 15.4 ± 7.4) once daily for empagliflozin. Among the paediatric cases of GSD Ib, empagliflozin 0.1-1.3 mg/kg/day improved neutropenia, infections, and gastrointestinal health. Dapagliflozin (mean dosage 6.9 ± 5.2 mg once daily) was well-tolerated in children with chronic kidney disease and heart failure. Side effects were generally mild, the most frequent being hypoglycaemia in children with GSD Ib (33% of patients) or T2DM (14% of patients) on concomitant hypoglycaemic drugs. Diabetic ketoacidosis is rare in children. CONCLUSION: Early evidence suggests that dapagliflozin and empagliflozin are well tolerated in children. A clinical pharmacology rationale currently exists only for adolescents with diabetes mellitus. PROSPERO REGISTRATION NUMBER: CRD42023438162.
Assuntos
Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Glucosídeos , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/farmacocinética , Humanos , Glucosídeos/uso terapêutico , Glucosídeos/efeitos adversos , Glucosídeos/farmacocinética , Glucosídeos/farmacologia , Glucosídeos/administração & dosagem , Criança , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , AdolescenteRESUMO
The aim of this study was to use a combination of physiologically based pharmacokinetic (PBPK) modeling and urinary glucose excretion (UGE) modeling to predict the time profiles of pharmacokinetics (PK) and UGE for the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMP). Additionally, the study aims to explore the compensatory effect of SGLT1 in renal glucose reabsorption (RGR) when SGLT2 is inhibited. The PBPK-UGE model was developed using physicochemical and biochemical properties, renal physiological parameters, binding kinetics, glucose, and Na+ reabsorption kinetics by SGLT1/2. For area under the plasma concentration-time curve, maximum plasma concentration, and cumulative EMP excretion in urine, the predicted values fell within a range of 0.5-2.0 when compared to observed data. Additionally, the simulated UGE data also matched well with the clinical data, further validating the accuracy of the model. According to the simulations, SGLT1 and SGLT2 contributed approximately 13% and 87%, respectively, to RGR in the absence of EMP. However, in the presence of EMP at doses of 2.5 and 10 mg, the contribution of SGLT1 to RGR significantly increased to approximately 76%-82% and 89%-93%, respectively, in patients with type 2 diabetes mellitus. Furthermore, the model supported the understanding that the compensatory effect of SGLT1 is the underlying mechanism behind the moderate inhibition observed in total RGR. The PBPK-UGE model has the capability to accurately predict the PK and UGE time profiles in humans. Furthermore, it provides a comprehensive analysis of the specific contributions of SGLT1 and SGLT2 to RGR in the presence or absence of EMP.
Assuntos
Compostos Benzidrílicos , Glucosídeos , Modelos Biológicos , Transportador 1 de Glucose-Sódio , Inibidores do Transportador 2 de Sódio-Glicose , Glucosídeos/farmacocinética , Humanos , Compostos Benzidrílicos/farmacocinética , Compostos Benzidrílicos/urina , Transportador 1 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Glucose/metabolismo , Masculino , Transportador 2 de Glucose-Sódio/metabolismo , Adulto , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Reabsorção Renal/efeitos dos fármacos , Rim/metabolismo , Glicosúria , Feminino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Empagliflozin is a sodium glucose co-transporter-2 (SGLT2) inhibitor that has gained significant attention in the treatment of type 2 diabetes mellitus. Understanding its chemistry, pharmacology, and toxicology is crucial for the safe and effective use of this medication. OBJECTIVE: This review aims to provide a comprehensive overview of the chemistry, pharmacology, and toxicology of empagliflozin, synthesizing the available literature to present a concise summary of its properties and implications for clinical practice. METHODS: A systematic search of relevant databases was conducted to identify studies and articles related to the chemistry, pharmacology, and toxicology of empagliflozin. Data from preclinical and clinical studies, as well as post-marketing surveillance reports, were reviewed to provide a comprehensive understanding of the topic. RESULTS: Empagliflozin is a selective SGLT2 inhibitor that works by constraining glucose reabsorption in the kidneys, causing increased urinary glucose elimination. Its unique mechanism of action provides glycemic control, weight reduction, and blood pressure reduction. The drug's chemistry is characterized by its chemical structure, solubility, and stability. Pharmacologically, empagliflozin exhibits favorable pharmacokinetic properties with rapid absorption, extensive protein binding, and renal elimination. Clinical studies have demonstrated its efficacy in improving glycemic control, reducing cardiovascular risks, and preserving renal function. However, adverse effects, for instance, urinary tract infections, genital infections, and diabetic ketoacidosis have been reported. Toxicological studies indicate low potential for organ toxicity, mutagenicity, or carcinogenicity. CONCLUSION: Empagliflozin is a promising SGLT2 inhibitor that offers an innovative approach to the treatment of type 2 diabetes mellitus. Its unique action mechanism and favorable pharmacokinetic profile contribute to its efficacy in improving glycemic control and reducing cardiovascular risks. While the drug's safety profile is generally favorable, clinicians should be aware of potential adverse effects and monitor patients closely. More study is required to determine the longterm safety and explore potential benefits in other patient populations. Overall, empagliflozin represents a valuable addition to the armamentarium of antidiabetic medications, offering significant benefits to patients suffering from type 2 diabetes mellitus. This study covers all aspects of empagliflozin, including its history, chemistry, pharmacology, and various clinical studies, case reports, and case series.
Assuntos
Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Glucosídeos , Hipoglicemiantes , Inibidores do Transportador 2 de Sódio-Glicose , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/farmacocinética , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/química , Humanos , Glucosídeos/uso terapêutico , Glucosídeos/farmacologia , Glucosídeos/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/química , Animais , Glicemia/efeitos dos fármacos , Transportador 2 de Glucose-SódioRESUMO
S-CE-123, a novel dopamine transporter inhibitor, has emerged as a potential candidate for cognitive enhancement. The objective of this study was to compare the tissue distribution profiles, with a specific focus on central nervous system distribution and metabolism, of S-CE-123 and R-modafinil. To address this objective, a precise liquid chromatography-high resolution mass spectrometry method was developed and partially validated. Neuropharmacokinetic parameters were assessed using the Combinatory Mapping Approach. Our findings reveal distinct differences between the two compounds. Notably, S-CE-123 demonstrates a significantly superior extent of transport across the blood-brain barrier (BBB), with an unbound brain-to-plasma concentration ratio (Kp,uu,brain) of 0.5, compared to R-modafinil's Kp,uu,brain of 0.1. A similar pattern was observed for the transport across the blood-spinal cord barrier. Concerning the drug transport across cellular membranes, we observed that S-CE-123 primarily localizes in the brain interstitial space, whereas R-modafinil distributes more evenly across both sides of the plasma membrane of the brain's parenchymal cells (Kp,uu,cell). Furthermore, our study highlights the substantial differences in hepatic metabolic stability, with S-CE-123 having a 9.3-fold faster metabolism compared to R-modafinil. In summary, the combination of improved BBB transport and higher affinity of S-CE-123 to dopamine transporters in comparison to R-modafinil makes S-CE-123 a promising candidate for further testing for the treatment of cognitive decline.
Assuntos
Compostos Benzidrílicos , Proteínas da Membrana Plasmática de Transporte de Dopamina , Compostos Benzidrílicos/metabolismo , Compostos Benzidrílicos/farmacocinética , Encéfalo/metabolismo , Sistema Nervoso Central/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Modafinila/metabolismoRESUMO
Bisphenol A (BPA) is one of the best studied industrial chemicals in terms of exposure, toxicity, and toxicokinetics. This renders it an ideal candidate to exploit the recent advancements in physiologically based pharmacokinetic (PBPK) modelling to support risk assessment of BPA specifically, and of other consumer-relevant hazardous chemicals in general. Using the exposure from thermal paper as a case scenario, this study employed the multi-phase multi-layer mechanistic dermal absorption (MPML MechDermA) model available in the Simcyp® Simulator to simulate the dermal toxicokinetics of BPA at local and systemic levels. Sensitivity analysis helped to identify physicochemical and physiological factors influencing the systemic exposure to BPA. The iterative modelling process was as follows: (i) development of compound files for BPA and its conjugates, (ii) setting-up of a PBPK model for intravenous administration, (iii) extension for oral administration, and (iv) extension for exposure via skin (i.e., hand) contact. A toxicokinetic study involving hand contact to BPA-containing paper was used for model refinement. Cumulative urinary excretion of total BPA had to be employed for dose reconstruction. PBPK model performance was verified using the observed serum BPA concentrations. The predicted distribution across the skin compartments revealed a depot of BPA in the stratum corneum (SC). These findings shed light on the role of the SC to act as temporary reservoir for lipophilic chemicals prior to systemic absorption, which inter alia is relevant for the interpretation of human biomonitoring data and for establishing the relationship between external and internal measures of exposure.
Assuntos
Absorção Cutânea , Pele , Humanos , Cinética , Pele/metabolismo , Compostos Benzidrílicos/toxicidade , Compostos Benzidrílicos/farmacocinéticaRESUMO
Evidence shows that sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, can delay the progressive decline of kidney function in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). We used a population pharmacokinetics (popPK) model to characterize the pharmacokinetics of dapagliflozin in patients with CKD and compare dapagliflozin systemic exposure in different populations, such as CKD with or without T2DM and T2DM without CKD. A 2-compartmental popPK model was developed from a previous popPK model. The final popPK model was based on 9715 dapagliflozin plasma concentrations from 3055 patients included in clinical studies involving adults with CKD with or without T2DM, adults with T2DM, healthy subjects, and pediatric patients with T2DM. Overall, the apparent clearance for patients treated with dapagliflozin was 21.6 L/h, similar to previous estimates in adults with T2DM and healthy subjects (22.9 L/h). Model-derived area under the plasma concentration-time curve (AUC) was not meaningfully different between patients with CKD with and without T2DM. Median AUC was 1.6-fold higher in adult patients with CKD with T2DM compared with adult patients with T2DM without CKD. Compared with patients with normal kidney function (estimated glomerular filtration rate ≥90 mL/min/1.73 m2 ), median AUC was 2.4-fold higher in patients with CKD (with/without T2DM) with estimated glomerular filtration rate 15-29 mL/min/1.73 m2 owing to decreased renal clearance of dapagliflozin. A higher AUC was observed in patients with a higher age or lower body weight but was not considered clinically relevant. This popPK model adequately described dapagliflozin pharmacokinetics and found that systemic exposure in patients with CKD was consistent, irrespective of T2DM status.
Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Adulto , Humanos , Criança , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Glucosídeos/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Compostos Benzidrílicos/farmacocinética , Taxa de Filtração GlomerularRESUMO
Bisphenol A (BPA) is a widely known endocrine disruptor (ED) found in many children's products such as toys, feeding utensils, and teething rings. Recent epidemiology association studies have shown postnatal BPA exposure resulted in developing various diseases such as diabetes, obesity, and neurodegeneration, etc., later in their lives. However, little is known about its sex-specific metabolism and consequently internal exposure. The aim of this study was to develop a sex-specific pediatric physiologically based pharmacokinetic model (PBPK) for BPA to compare their toxicokinetic differences. First, the published adult PBPK model was re-validated, and then this model was extended by interpolation to incorporate pediatric sex specific physiological and biochemical parameters. We used both the classical body weight and ontogeny-based scaling approach to interpolate the metabolic process. Then, the pharmacokinetic attributes of the models using the two-scaling approach mentioned above were compared with adult model. Further, a sex-specific PBPK model with an ontogeny scaling approach was preferred to evaluate the pharmacokinetic differences. Moreover, this model was used to reconstruct the BPA exposure from two cohorts (Helix and PBAT Cohort) from 7 EU countries. The half-life of BPA was found to be almost the same in boys and girls at the same exposure levels. Our model estimated BPA children's exposure to be about 1500 times higher than the tolerable daily intake (TDI) recently set by European Food Safety Authority (EFSA) i.e., 0.04 ng/kg BW/day. The model demonstrated feasibility of extending the adult PBPK to sex-specific pediatric, thus investigate a gender-specific health risk assessment.
Assuntos
Disruptores Endócrinos , Adulto , Compostos Benzidrílicos/farmacocinética , Compostos Benzidrílicos/toxicidade , Criança , Disruptores Endócrinos/farmacocinética , Disruptores Endócrinos/toxicidade , Feminino , Humanos , Masculino , Fenóis/farmacocinética , Fenóis/toxicidade , ToxicocinéticaRESUMO
Dapagliflozin improves glycemic control in patients with type 2 diabetes mellitus (T2DM) and is approved in Japanese patients with type 1 diabetes mellitus (T1DM) with inadequate glycemic control. The objectives of this work were to characterize the dapagliflozin pharmacokinetics (PK) in patients with T1DM, assess the influence of covariates on dapagliflozin PK, and compare dapagliflozin systemic exposure between patients with T1DM and T2DM. Population PK analysis was performed using a nonlinear mixed-effect modeling approach. The analysis included 5793 dapagliflozin plasma concentrations from 1150 adult patients with T1DM (global population), who were on routine insulin therapy, collected from 1 phase 2 (NCT01498185) and 2 phase 3 (DEPICT-1, NCT02268214; DEPICT-2, NCT02460978) studies. Covariate effects were investigated using stepwise covariate modeling. Model-derived area under the concentration-time curve (AUC) in patients with T1DM was compared to AUC in patients with T2DM (using data from historical dapagliflozin studies). The final 2-compartmental model adequately described the dapagliflozin concentrations in patients with T1DM. The estimated apparent clearance was 20.5 L/h. Renal function (measured as estimated glomerular filtration rate), sex, and body weight were identified as covariates, where patients with better renal function, male patients, and heavier patients had lower dapagliflozin systemic exposure. Among the covariates studied, none of the covariates affected dapagliflozin systemic exposure >1.4-fold compared to a reference individual and were therefore deemed to be not clinically relevant. Dapagliflozin systemic exposure was comparable between patients with T1DM and T2DM.
Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Adulto , Compostos Benzidrílicos/farmacocinética , Glicemia/análise , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Relação Dose-Resposta a Droga , Feminino , Glucosídeos , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , MasculinoRESUMO
Complement-mediated intravascular hemolysis occurs in canine immune-mediated hemolytic anemia (IMHA). Complement inhibitors might enhance treatment of this disease. Dimers of acetylsalicylic acid such as 5,5'-methylenebis(2-acetoxybenzoic acid) (DAS) have been reported to inhibit complement. This study aimed to characterize the pharmacokinetics and safety profile of a single 3 mg/kg IV dose of DAS in 6 healthy mixed-breed dogs. Serum concentrations of DAS and its primary metabolites were measured by liquid chromatography-tandem mass spectrometry at baseline and at 5, 10 and 30 min, and 1, 2, 4, 6, 8, 12, 18 and 24 h post-administration. Additional blood samples were collected 7 and 14 days after drug administration. Complete blood counts, serum chemistry panels, C-reactive protein measurements, coagulation testing and cytokine analyses were used for safety monitoring. Following IV administration of 3 mg/kg DAS, the estimated mean maximum plasma concentration was 54,709 ng/mL. Pharmacokinetic modeling suggested that DAS was eliminated with a half-life value of 8.1 h, equivalent to a clearance of 6.93 L/hr kg and a volume of distribution of 56 mL/kg. Plasma concentrations of the metabolites were measured rapidly (within 15-60 min for M1 and M2 respectively). Overall, the relative exposure to M1 and M2 suggest significant biotransformation of DAS occurred, but DAS was the most abundant circulating species. No adverse clinical reactions were noted following DAS administration and safety studies suggested DAS caused no inflammatory response or coagulation disturbance. Further clinical evaluation of DAS is warranted.
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Aspirina/análogos & derivados , Compostos Benzidrílicos/farmacocinética , Animais , Aspirina/farmacocinética , Cromatografia Líquida/veterinária , Cães , Infusões Intravenosas/veterinária , CinéticaAssuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/farmacocinética , Ensaios Clínicos como Assunto/métodos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Glucosídeos/farmacocinética , Humanos , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinéticaRESUMO
Background Sodium-glucose cotransporter 2 inhibitors reduce hospitalizations for heart failure and cardiovascular death, although the underlying mechanisms have not been resolved. The SIMPLE trial (The Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus) investigated the effects of empagliflozin on myocardial flow reserve (MFR) reflecting microvascular perfusion, in patients with type 2 diabetes mellitus at high cardiovascular disease risk. Methods and Results We randomized 90 patients to either empagliflozin 25 mg once daily or placebo for 13 weeks, as add-on to standard therapy. The primary outcome was change in MFR at week 13, quantified by Rubidium-82 positron emission tomography/computed tomography. The secondary key outcomes were changes in resting rate-pressure product adjusted MFR, changes to myocardial flow during rest and stress, and reversible cardiac ischemia. Mean baseline MFR was 2.21 (95% CI, 2.08-2.35). There was no change from baseline in MFR at week 13 in either the empagliflozin: 0.01 (95% CI, -0.18 to 0.21) or placebo groups: 0.06 (95% CI, -0.15 to 0.27), with no treatment effect -0.05 (95% CI, -0.33 to 0.23). No effects on the secondary outcome parameters by Rubidium-82 positron emission tomography/computed tomography was observed. Treatment with empagliflozin reduced hemoglobin A1c by 0.76% (95% CI, 1.0-0.5; P<0.001) and increased hematocrit by 1.69% (95% CI, 0.7-2.6; P<0.001). Conclusions Empagliflozin did not improve MFR among patients with type 2 diabetes mellitus and high cardiovascular disease risk. The present study does not support that short-term improvement in MFR explains the reduction in cardiovascular events observed in the outcome trials. Registration URL: https://clinicaltrialsregister.eu/; Unique identifier: 2016-003743-10.
Assuntos
Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Reserva Fracionada de Fluxo Miocárdico/efeitos dos fármacos , Glucosídeos , Hemoglobinas Glicadas/análise , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/farmacocinética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Glucosídeos/administração & dosagem , Glucosídeos/farmacocinética , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Microcirculação/efeitos dos fármacos , Pessoa de Meia-Idade , Imagem de Perfusão do Miocárdio/métodos , Resultados Negativos , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinéticaRESUMO
PURPOSE: Combination therapy with insulin-independent sodium-glucose cotransporter 2 inhibitors and thiazolidinedione drugs, such as lobeglitazone, has been reported to elicit potential additive efficacy in glycemic control in type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetic (PK) drug-drug interactions between empagliflozin and lobeglitazone in healthy subjects. SUBJECTS AND METHODS: A randomized, open-label, multiple-dose study was conducted in 30 healthy subjects using a three-treatment, six-sequence, three-way crossover design. Subjects received one of the following treatments once daily for 5 days in each period: 25 mg empagliflozin, 0.5 mg lobeglitazone sulfate, or a combination. Serial blood sampling before every dose and up to 24 h after the last dose was performed during each treatment period. The PK parameters were estimated using noncompartmental methods with the plasma empagliflozin and lobeglitazone concentrations. The absence of a PK interaction was construed as the 90% confidence interval (90% CI) of maximum concentration at steady state (Cmax,ss) and area under the concentration-time curve over the dosing interval (AUCtau) for combination therapy-to-monotherapy ratios within the limits of 0.80-1.25. RESULTS: The steady-state plasma empagliflozin and lobeglitazone concentration-time profiles of combination therapy and monotherapy were comparable in the 25 subjects who completed the study. Coadministration of empagliflozin with lobeglitazone did not affect empagliflozin PK (with 90% CIs of 0.956-1.150 and 0.945-1.133 for Cmax,ss and AUCtau, respectively). Likewise, empagliflozin did not affect lobeglitazone Cmax,ss or AUCtau (with 90% CIs of 0.869-0.995 and 0.851-1.018, respectively). All treatment groups tolerated mild adverse events well. CONCLUSION: The lack of PK interactions between lobeglitazone and empagliflozin in combination therapy, along with their good tolerability, indicates that the two drugs can be coadministered without dose adjustment. TRIAL REGISTRATION NUMBER: NCT02854748, Registered on August 7, 2016.
Assuntos
Compostos Benzidrílicos/farmacocinética , Glucosídeos/farmacocinética , PPAR gama/agonistas , Pirimidinas/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Tiazolidinedionas/farmacocinética , Administração Oral , Adulto , Compostos Benzidrílicos/administração & dosagem , Interações Medicamentosas , Tolerância a Medicamentos , Glucosídeos/administração & dosagem , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Tiazolidinedionas/administração & dosagem , Adulto JovemRESUMO
This analysis reports a quantitative modeling and simulation approach for oral dapagliflozin, a primarily uridine diphosphate-glucuronosyltransferase (UGT)-metabolized human sodium-glucose cotransporter 2 selective inhibitor. A mechanistic dapagliflozin physiologically based pharmacokinetic (PBPK) model was developed using in vitro metabolism and clinical pharmacokinetic (PK) data and verified for context of use (e.g., exposure predictions in pediatric subjects aged 1 month to 18 years). Dapagliflozin exposure is challenging to predict in pediatric populations owing to differences in UGT1A9 ontogeny maturation and paucity of clinical PK data in younger age groups. Based on the exposure-response relationship of dapagliflozin, twofold acceptance criteria were applied between model-predicted and observed drug exposures and PK parameters (area under the curve and maximum drug concentration) in various scenarios, including monotherapy in healthy adults (single/multiple dose), monotherapy in hepatically or renally impaired patients, and drug-drug interactions with UGT1A9 modulators, such as mefenamic acid and rifampin. The PBPK model captured the observed exposure within twofold of the observed monotherapy data in adults and adolescents and in special population. As a guide to determining dosing regimens in pediatric studies, the verified PBPK model, along with UGT enzyme ontogeny maturation understanding, was used for predictions of dapagliflozin monotherapy exposures in pediatric subjects aged 1 month to 18 years that best matched exposure in adult patients with a 10-mg single dose of dapagliflozin.
Assuntos
Compostos Benzidrílicos/farmacocinética , Glucosídeos/farmacocinética , Glucuronosiltransferase/metabolismo , Ácido Mefenâmico/farmacocinética , Rifampina/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , UDP-Glucuronosiltransferase 1A/metabolismo , Administração Oral , Adolescente , Antibióticos Antituberculose/administração & dosagem , Antibióticos Antituberculose/efeitos adversos , Antibióticos Antituberculose/farmacocinética , Área Sob a Curva , Criança , Pré-Escolar , Simulação por Computador , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/efeitos adversos , Inibidores de Ciclo-Oxigenase/farmacocinética , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Voluntários Saudáveis/estatística & dados numéricos , Insuficiência Hepática/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Masculino , Ácido Mefenâmico/administração & dosagem , Ácido Mefenâmico/efeitos adversos , Modelos Biológicos , Valor Preditivo dos Testes , Insuficiência Renal/tratamento farmacológico , Rifampina/administração & dosagem , Rifampina/efeitos adversosRESUMO
We investigated the plasma toxicokinetic behavior of free (parent) and total (parent and conjugated forms) of bisphenol S (BPS) and bisphenol AF (BPAF) in plasma of adult male rats and mice following exposure via feed for 7 days to BPS (338, 1125, and 3375 ppm) or BPAF (338, 1125, and 3750 ppm). In rats, the exposure concentration-normalized maximum concentration [Cmax/D (ng/mL)/(ppm)] and area under the concentration time curve [AUC/D (h × ng/mL)/(ppm)] for free was higher for BPS (Cmax/D: 0.476-1.02; AUC/D: 3.58-8.26) than for BPAF (Cmax/D: 0.017-0.037; AUC/D:0.196-0.436). In mice, the difference in systemic exposure parameters between free BPS (Cmax/D: 0.376-0.459; AUC/D: 1.52-2.54) and free BPAF (Cmax/D: 0.111-0.165; AUC/D:0.846-1.09) was marginal. Elimination half-lives for free analytes (4.41-10.4 h) were comparable between species and analogues. When systemic exposure to free analyte was compared between species, in rats, BPS exposure was slightly higher but BPAF exposure was much lower than in mice. BPS and BPAF were highly conjugated; total BPS AUC values (rats ≥18-fold, mice ≥17-fold) and BPAF (rats ≥127-fold, mice ≥16-fold) were higher than corresponding free values. Data demonstrated that there are analogue and species differences in the kinetics of BPS and BPAF.
Assuntos
Compostos Benzidrílicos/farmacocinética , Substâncias Perigosas/farmacocinética , Fenóis/farmacocinética , Sulfonas/farmacocinética , Animais , Compostos Benzidrílicos/toxicidade , Substâncias Perigosas/toxicidade , Cinética , Masculino , Camundongos , Fenóis/toxicidade , Ratos , Sulfonas/toxicidade , Testes de Toxicidade , ToxicocinéticaRESUMO
Control of hyperglycemia and prevention of glucose reabsorption (glucotoxicity) are important objectives in the management of type 2 diabetes. This study deals with an oral combined dosage form design for two anti-diabetic drugs, sitagliptin and dapagliflozin using self-nanoemulsifying drug delivery systems (SNEDDS). The SNEDDS were developed using naturally obtained bioactive medium-chain/long-chain triglycerides oil, mixed glycerides and nonionic surfactants, and droplet size was measured followed by the test for antioxidant activities. Equilibrium solubility and dynamic dispersion experiments were conducted to achieve the maximum drug loading. The in vitro digestion, in vivo bioavailability, and anti-diabetic effects were studied to compare the representative SNEDDS with marketed product Dapazin®. The representative SNEDDS containing black seed oil showed excellent self-emulsification performance with transparent appearance. Characterization of the SNEDDS showed nanodroplets of around 50-66.57 nm in size (confirmed by TEM analysis), in addition to the high drug loading capacity without causing any precipitation in the gastro-intestinal tract. The SNEDDS provided higher antioxidant activity compared to the pure drugs. The in vivo pharmacokinetic parameters of SNEDDS showed significant increase in C max (1.99 ± 0.21 µg mL-1), AUC (17.94 ± 1.25 µg mL-1), and oral absorption (2-fold) of dapagliflozin compared to the commercial product in the rat model. The anti-diabetic studies showed the significant inhibition of glucose level in treated diabetic mice by SNEDDS combined dose compared to the single drug therapy. The combined dose of sitagliptin-dapagliflozin using SNEDDS could be a potential oral pharmaceutical product for the improved treatment of type 2 diabetes mellitus.
Assuntos
Compostos Benzidrílicos/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Emulsões/química , Glucosídeos/administração & dosagem , Nanopartículas/química , Fosfato de Sitagliptina/administração & dosagem , Animais , Área Sob a Curva , Compostos Benzidrílicos/farmacocinética , Química Farmacêutica , Diabetes Mellitus Tipo 2/tratamento farmacológico , Combinação de Medicamentos , Liberação Controlada de Fármacos , Glucosídeos/farmacocinética , Hipoglicemiantes , Masculino , Taxa de Depuração Metabólica , Camundongos , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Óleos de Plantas/química , Ratos , Ratos Wistar , Fosfato de Sitagliptina/farmacocinética , Solubilidade , Propriedades de SuperfícieRESUMO
Sodium-dependent glucose transporter (SGLT) 2 is specifically expressed in the kidney, while SGLT1 is present in the kidneys and small intestine. SGLT2 inhibitors are a class of oral antidiabetic drugs that lower elevated plasma glucose levels by promoting the urinary excretion of excess glucose through the inhibition of renal glucose reuptake. The inhibition selectivity for SGLT2 over SGLT1 (SGLT2/1 selectivity) of marketed SGLT2 inhibitors is diverse, while SGLT2/1 selectivity of canagliflozin is relatively low. Although canagliflozin suppresses postprandial glucose levels, the degree of contribution for SGLT1 inhibition to this effect remains unproven. To analyze the effect of SGLT2 inhibitors on postprandial glucose level, we constructed a novel quantitative systems pharmacology (QSP) model, called human systemic glucose dynamics (HSGD) model, integrating intestinal absorption, metabolism, and renal reabsorption of glucose. This HSGD model reproduced the postprandial plasma glucose concentration-time profiles during a meal tolerance test under different clinical trial conditions. Simulations after canagliflozin administration showed a dose-dependent delay of time (Tmax,glc ) to reach maximum concentration of glucose (Cmax,glc ), and the delay of Tmax,glc disappeared when inhibition of SGLT1 was negated. In addition, contribution ratio of intestinal SGLT1 inhibition to the decrease in Cmax,glc was estimated to be 23%-28%, when 100 and 300 mg of canagliflozin are administered. This HSGD model enabled us to provide the partial contribution of intestinal SGLT1 inhibition to the improvement of postprandial hyperglycemia as well as to quantitatively describe the plasma glucose dynamics following SGLT2 inhibitors.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Modelos Biológicos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Adulto , Compostos Benzidrílicos/farmacocinética , Compostos Benzidrílicos/farmacologia , Canagliflozina/farmacocinética , Canagliflozina/farmacologia , Feminino , Glucosídeos/farmacocinética , Glucosídeos/farmacologia , Humanos , Absorção Intestinal , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Pirazóis/farmacocinética , Pirazóis/farmacologia , Fosfato de Sitagliptina/farmacocinética , Fosfato de Sitagliptina/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Tiazolidinas/farmacocinética , Tiazolidinas/farmacologia , Tiofenos/farmacocinética , Tiofenos/farmacologia , Adulto JovemRESUMO
Leachables from pharmaceutical container closure systems are a subset of impurities that present in drug products and may pose a risk to patients or compromise product quality. Extractable studies can identify potential leachables, and extractables and leachables (E&Ls) should be evaluated during development of the impurity control strategy. Currently, there is a lack of specific regulatory guidance on how to risk assess E&Ls; this may lead to inconsistency across the industry. This manuscript is a cross-industry Extractables and Leachables Safety Information Exchange (ELSIE) consortium collaboration and follow-up to Broschard et al. (2016), which aims to provide further clarity and detail on the conduct of E&L risk assessments. Where sufficient data are available, a health-based exposure limit termed Permitted Daily Exposure (PDE) may be calculated and to exemplify this, case studies of four common E&Ls are described herein, namely bisphenol-A, butylated hydroxytoluene, Irgafos® 168, and Irganox® 1010. Relevant discussion points are further explored, including the value of extractable data, how to perform route-to-route extrapolations and considerations around degradation products. By presenting PDEs for common E&L substances, the aim is to encourage consistency and harmony in approaches for deriving compound-specific limits.