RESUMEN
Dapagliflozin was recently approved for use in adults with chronic heart failure with reduced ejection fraction (HFrEF) with/without type 2 diabetes mellitus (T2DM). The objectives of this analysis were to characterize dapagliflozin pharmacokinetics in patients with HFrEF and to compare dapagliflozin systemic exposure between adults with HFrEF with/without T2DM and adults with T2DM. A nonlinear mixed-effects modelling approach was applied; the population-pharmacokinetic model was developed using 9735 dapagliflozin plasma concentrations from 2744 patients. The final two-compartmental model adequately described the observed dapagliflozin concentrations, with a similar estimated apparent clearance compared with a previous estimate in patients with T2DM without HF and in healthy subjects (23.0 [95% CI: 22.6-23.9] L/h vs. 22.9 [95% CI: 22.1-23.7] L/h). The model-predicted median area under the dapagliflozin concentration-time profile was ≤1.2-fold higher in patients with HFrEF vs. those with T2DM without HFrEF, which is not considered clinically relevant. Dapagliflozin exposure was similar between patients with HFrEF with/without T2DM and T2DM patients without HFrEF.
Asunto(s)
Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Adulto , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/inducido químicamente , Volumen Sistólico , Glucósidos/efectos adversos , Compuestos de Bencidrilo/efectos adversos , Disfunción Ventricular Izquierda/inducido químicamenteRESUMEN
AIMS: To use population physiologically based pharmacokinetic (PopPBPK) modelling to optimize target expression, kinetics and clearance of HER1/2 directed therapeutic monoclonal antibodies (mAbs). Thus, to propose a general workflow of PopPBPK modelling and its application in clinical pharmacology. METHODS: Full PBPK model of pertuzumab (PTZ) was developed in patient population using Simcyp V21R1 incorporating mechanistic targeted-mediated drug disposition process by fitting known clinical PK and sparse receptor proteomics data to optimize target expression and kinetics of HER2 receptor. Trastuzumab (TTZ) PBPK modelling was used to validate the optimized HER2 target. Additionally, the simulator was also used to develop a full PBPK model for the HER1-directed mAb cetuximab (CTX) to assess the underlying targeted-mediated drug disposition-independent elimination mechanisms. RESULTS: HER2 final parameterisation coming from the PBPK modelling of PTZ was successfully cross validated through PBPK modelling of TTZ with average fold error (AFE), absolute AFE and percent prediction error values for area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ) of 1.13, 1.16 and 16, and 1.01, 1.07 and 7, respectively. CTX PBPK model performance was validated after the incorporation of an additional systemic clearance of 0.033 L/h as AFE and absolute AFE showed an acceptable predictive power of AUC and Cmax with percent prediction error of 13% for AUC and 10% for Cmax . CONCLUSIONS: Optimisation of both system and drug related parameters were performed through PBPK modelling to improve model performance of therapeutic mAbs (PTZ, TTZ and CTX). General workflow was proposed to develop and apply PopPBPK to support clinical development of mAbs targeting same receptor.
Asunto(s)
Anticuerpos Monoclonales , Modelos Biológicos , Humanos , Anticuerpos Monoclonales/farmacocinética , Cinética , Simulación por Computador , Trastuzumab , CetuximabRESUMEN
Dapagliflozin is an inhibitor of human renal sodium-glucose cotransporter 2 (SGLT2), first approved for the treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin is primarily metabolized by uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9). The effect of UGT1A9 polymorphisms on dapagliflozin apparent oral clearance (CL/F) was studied with dapagliflozin population pharmacokinetic data and UGT1A9 genotype data (I.399C>T, rs2011404, rs6759892, rs7577677, rs4148323, UGT1A9*2 and UGT1A9*3) from a Phase 2 study conducted in subjects with T2DM (n = 187). An analysis of covariance (ANCOVA) model accounting for known covariates influencing dapagliflozin CL/F was applied to these data to quantify the impact of each UGT1A9 polymorphism relative to the wildtype UGT1A9 genotype. The analysis showed that the geometric mean ratios of dapagliflozin CL/F for all of the UGT1A9 polymorphisms studied were within the range of wildtype UGT1A9 CL/F values. Consequently, the polymorphisms of UGT1A9 studied had no clinically meaningful impact on the CL/F of dapagliflozin.
Asunto(s)
Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Compuestos de Bencidrilo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Glucósidos , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Humanos , Hipoglucemiantes , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacocinética , UDP Glucuronosiltransferasa 1A9RESUMEN
BACKGROUND: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined the efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy after randomization to dapagliflozin or placebo. METHODS: We examined the effects of study treatment in the following subgroups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline. We examined the primary composite end point of cardiovascular death or a worsening heart failure event and its components, all-cause death and symptoms. RESULTS: Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on <40 mg, 1365 (29.6%) were on 40 mg, and 1204 (26.1%) were taking >40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary end point across each of these subgroups: hazard ratios were 0.57 (95% CI, 0.36-0.92), 0.83 (95% CI, 0.63-1.10), 0.77 (95% CI, 0.60-0.99), and 0.78 (95% CI, 0.63-0.97), respectively (P for interaction=0.61). The hazard ratio in patients taking any diuretic was 0.78 (95% CI, 0.68-0.90). Improvements in symptoms and treatment toleration were consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow-up, and mean diuretic dose did not differ between the dapagliflozin and placebo groups after randomization. CONCLUSIONS: The efficacy and safety of dapagliflozin were consistent across the diuretic subgroups examined in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
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Compuestos de Bencidrilo/administración & dosificación , Diuréticos/administración & dosificación , Glucósidos/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Volumen Sistólico/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIM: To provide evidence on the cardiovascular and renal safety of metformin in chronic kidney disease (CKD) stages 3 to 4. MATERIALS AND METHODS: This post hoc analysis compared participants with an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73m2 in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) and the Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (SAVOR-TIMI 53) trials taking metformin, with those not exposed to metformin during these trials, using a propensity-matching approach. Adjusted Cox proportional hazards models were used to assess risk of major adverse cardiovascular events (MACE) and all-cause mortality (ACM). Metformin effect on eGFR slope was calculated using a mixed-model repeated measures analysis, and the number of lactic acidosis events was tabulated. RESULTS: No strong trend for lower metformin doses with lower eGFR values was observed in either the EXSCEL or SAVOR-TIMI 53 trials. In the 1745 metformin-using participants matched to non-metformin users, metformin had neutral effects on MACE (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.76-1.08; P = 0.28) and ACM (HR 0.86, 95% CI 0.70-1.07; P = 0.18), with no interaction by CKD stage, or with use of exenatide or saxagliptin. An improvement in eGFR slope was observed with metformin in the CKD stage 3B cohort in SAVOR-TIMI 53, but not in other groups. CONCLUSIONS: This analysis of participants with CKD stages 3 to 4 from two cardiovascular outcomes trials supports the cardiorenal safety of metformin, but does not suggest a consistent benefit on MACE, ACM, or eGFR slope across this population.
Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Metformina , Insuficiencia Renal Crónica , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Tasa de Filtración Glomerular , Humanos , Riñón , Metformina/efectos adversos , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/epidemiologíaRESUMEN
Sodium glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular events and onset and progression of renal disease by mechanisms that remain incompletely understood but may include clearance of interstitial congestion and reduced glomerular hydrostatic pressure. The ongoing DAPASALT mechanistic clinical study will evaluate natriuretic, diuretic, plasma/extracellular volume, and blood pressure responses to dapagliflozin in people with type 2 diabetes with normal or impaired renal function (D-PRF and D-IRF, respectively) and in normoglycemic individuals with renal impairment (N-IRF). In this study, a mathematical model of renal physiology, pathophysiology, and pharmacology was used to prospectively predict changes in sodium excretion, blood and interstitial fluid volume (IFV), blood pressure, glomerular filtration rate, and albuminuria in DAPASALT. After validating the model with previous diabetic nephropathy trials, virtual patients were matched to DAPASALT inclusion/exclusion criteria, and the DAPASALT protocol was simulated. Predicted changes in glycosuria, blood pressure, glomerular filtration rate, and albuminuria were consistent with other recent studies in similar populations. Predicted albuminuria reductions were 46% in D-PRF, 34.8% in D-IRF, and 14.2% in N-IRF. The model predicts a similarly large IFV reduction between D-PRF and D-IRF and less, but still substantial, IFV reduction in N-IRF, even though glycosuria is attenuated in groups with impaired renal function. When DAPASALT results become available, comparison with these simulations will provide a basis for evaluating how well we understand the cardiorenal mechanism(s) of SGLT2i. Meanwhile, these simulations link dapagliflozin's renal mechanisms to changes in IFV and renal biomarkers, suggesting that these benefits may extend to those with impaired renal function and individuals without diabetes. SIGNIFICANCE STATEMENT: Mechanisms of SGLT2 inhibitors' cardiorenal benefits remain incompletely understood. We used a mathematical model of renal physiology/pharmacology to prospectively predict responses to dapagliflozin in the ongoing DAPASALT study. Key predictions include similarly large interstitial fluid volume (IFV) reductions between subjects with normal and impaired renal function and less, but still substantial, IFV reduction in those without diabetes, even though glycosuria is attenuated in these groups. Comparing prospective simulations and study results will assess how well we understand the cardiorenal mechanism(s) of SGLT2 inhibitors.
Asunto(s)
Compuestos de Bencidrilo/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/fisiopatología , Tasa de Filtración Glomerular/efectos de los fármacos , Glucósidos/uso terapéutico , Riñón/efectos de los fármacos , Modelos Biológicos , Insuficiencia Renal/fisiopatología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Compuestos de Bencidrilo/efectos adversos , Ensayos Clínicos Fase IV como Asunto , Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/metabolismo , Tasa de Filtración Glomerular/fisiología , Glucósidos/efectos adversos , Humanos , Riñón/metabolismo , Riñón/fisiopatología , Ensayos Clínicos Controlados Aleatorios como Asunto , Insuficiencia Renal/metabolismo , Índice de Severidad de la Enfermedad , Transportador 2 de Sodio-Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversosRESUMEN
AIM: To assess whether the previously developed multivariable risk prediction framework (PRE score) could predict the renal effects observed in the EXSCEL cardiovascular outcomes trial using short-term changes in cardio-renal risk markers. MATERIALS AND METHODS: Changes from baseline to 6 months in HbA1c, systolic blood pressure (SBP), body mass index (BMI), haemoglobin, total cholesterol, and new micro- or macroalbuminuria were evaluated. The renal outcomes were defined as a composite of a sustained 30% or 40% decline in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD). Relationships between risk markers and long-term renal outcomes were determined in patients with type 2 diabetes from the ALTITUDE study using multivariable Cox regression analysis, and then applied to short-term changes in risk markers observed in EXSCEL to predict the exenatide-induced impact on renal outcomes. RESULTS: Compared with placebo, mean HbA1c, BMI, SBP and total cholesterol were lower at 6 months with exenatide, as was the incidence of new microalbuminuria. The PRE score predicted a relative risk reduction for the 30% eGFR decline + ESRD endpoint of 11.3% (HR 0.89; 95% CI 0.83-0.94), compared with 12.7% (HR 0.87; 0.77-0.99) observed risk reduction. For the 40% eGFR decline + ESRD endpoint, the predicted and observed risk reductions were 11.0% (HR 0.89; 0.82-0.97) and 13.7% (HR 0.86, 0.72-1.04), respectively. CONCLUSIONS: Integrating short-term risk marker changes into a multivariable risk score predicted the magnitude of renal risk reduction observed in EXSCEL.
Asunto(s)
Diabetes Mellitus Tipo 2 , Enfermedades Renales , Albuminuria/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Progresión de la Enfermedad , Exenatida/uso terapéutico , Tasa de Filtración Glomerular , Humanos , Factores de RiesgoRESUMEN
The effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on renal outcomes in patients with type 2 diabetes at high cardiovascular risk are modest or neutral. However, GLP-1RAs may confer clinical benefits in those at high risk of progressive renal function loss. We examined the effects of once-weekly exenatide (EQW) on estimated glomerular filtration rate (eGFR) slope and urinary albumin:creatinine ratio (UACR) as a function of baseline UACR in 3503 EXSCEL participants (23.7%) with eGFR data available and 2828 participants (19.2%) with UACR change data available. EQW improved eGFR slope assessed via mixed model repeated measures, compared with placebo, in participants with baseline UACR >100 mg/g (0.79 mL/min/1.73 m2 /year [95% confidence interval {CI} 0.24-1.34]) and UACR >200 mg/g (1.32 mL/min/1.73 m2 /year [95% CI 0.57-2.06]), but not at lower UACR thresholds. EQW reduced UACR, compared with placebo, assessed via analysis of covariance, consistently across subgroups with baseline UACR >30 mg/g (28.2% reduction), baseline UACR >100 mg (22.5% reduction) and baseline UACR >200 mg (34.5% reduction). This post hoc EXSCEL analysis suggests that EQW reduces UACR, with improvement in eGFR slope specifically in participants with elevated baseline UACR.
Asunto(s)
Diabetes Mellitus Tipo 2 , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Exenatida , Tasa de Filtración Glomerular , Humanos , Riñón , Pruebas de Función RenalRESUMEN
BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes. METHODS: In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses. RESULTS: In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39-1.17) and EQW alone (0.85, 0.48-1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16-0.90) and compared with EQW (0.41, 0.17-0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94-2.94 mL/min/1.73 m2/year) and EQW alone (+ 2.38, 1.40-3.35 mL/min/1.73 m2/year). CONCLUSIONS: This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010.
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Exenatida/administración & dosificación , Tasa de Filtración Glomerular/efectos de los fármacos , Incretinas/administración & dosificación , Riñón/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Anciano , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/fisiopatología , Causas de Muerte , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/fisiopatología , Esquema de Medicación , Quimioterapia Combinada , Exenatida/efectos adversos , Femenino , Humanos , Incretinas/efectos adversos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Factores de Riesgo , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIMS: To quantitatively describe the relationship between dapagliflozin systemic exposure and HbA1c response among patients with type 1 diabetes mellitus (T1DM) and assess the potential impact of covariate effects. MATERIALS AND METHODS: Individual longitudinal HbA1c data from two phase 3 studies in patients with T1DM (24-week treatment with once-daily dapagliflozin 5 or 10 mg or placebo, with adjustable insulin) were analyzed using a non-linear mixed effect modeling approach. Area under the concentration curve was used to measure dapagliflozin systemic exposure. Baseline HbA1c, estimated glomerular filtration rate, reduction in total insulin dose, baseline glucose concentrations, age, sex, race (Asian vs. non-Asian), and insulin administration method (multiple daily injections vs. insulin pump) were assessed as covariates. RESULTS: A maximum effect (Emax ) model identified a positive exposure-response relationship. Model-predicted placebo-corrected HbA1c reductions after 24 weeks for dapagliflozin 5- and 10-mg doses were - 0.42% [95% confidence interval (CI) -0.47 to -0.36) and - 0.45% (95% CI -0.50 to -0.40), respectively; baseline HbA1c was ~8.4%. This was in good agreement with actual observations from both studies. Baseline HbA1c was a significant covariate: patients with higher baseline HbA1c were predicted to have greater HbA1c reductions. CONCLUSIONS: The relationship between dapagliflozin systemic exposure and HbA1c response was successfully described in patients with T1DM. None of the tested covariates affected the efficacy of dapagliflozin to a clinically relevant extent. Therefore, no dose adjustment of dapagliflozin is required in patients with T1DM based on the tested covariates. ClinicalTrials.gov, NCT02268214; NCT02460978.
Asunto(s)
Compuestos de Bencidrilo , Diabetes Mellitus Tipo 1 , Glucósidos , Hemoglobina Glucada/análisis , Adolescente , Adulto , Anciano , Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/uso terapéutico , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Femenino , Tasa de Filtración Glomerular , Glucósidos/administración & dosificación , Glucósidos/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
AIMS: To assess the pharmacokinetics/pharmacodynamics (PK/PD) of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor that increases urinary glucose excretion (UGE) and its major metabolite, dapagliflozin-3-O-glucuronide (D3OG), in Japanese patients with type 1 diabetes (T1D) and inadequate glycaemic control (HbA1c 7%-10%). MATERIALS AND METHODS: Japanese patients (18-65 years) with inadequately controlled T1D were randomized 1:1:1 to dapagliflozin 5 mg, 10 mg or placebo (n = 14 each) once daily for 7 days, with adjustable insulin. The PK/PD characteristics of dapagliflozin and D3OG were assessed on Day 7. Patients underwent follow-up evaluation on Days 8 and 14. Adverse events (AEs), hypoglycaemic episodes and events of diabetic ketoacidosis (DKA) were recorded over the treatment and follow-up periods. RESULTS: A total of 42 randomized patients received dapagliflozin or placebo. PK variables increased in a dose-dependent manner. D3OG was generated rapidly, with a median time to maximum plasma concentration of 2.0 hours (1.0-3.0). The dapagliflozin dose-UGE relationship was attenuated, with larger insulin dose reductions than anticipated. Mean percent (standard error) changes in total daily insulin dose from baseline to Day 7 were - 36.86% (3.32), -39.13% (2.68) and - 4.97% (5.28) for dapagliflozin 5 mg and 10 mg and for placebo, respectively. No DKA was reported. AEs were consistent with the established dapagliflozin safety profile. There was no increase in hypoglycaemia. CONCLUSIONS: The PK and safety profiles of dapagliflozin in Japanese patients with T1D were consistent with previous studies, but with an unanticipated attenuation of the PD dose-response measured as UGE.
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Compuestos de Bencidrilo/farmacocinética , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Glucósidos/farmacocinética , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacocinética , Adulto , Compuestos de Bencidrilo/farmacología , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Glucósidos/farmacología , Glucurónidos/sangre , Glucosuria/orina , Humanos , Japón , Masculino , Persona de Mediana Edad , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacologíaRESUMEN
AIMS: To assess the dapagliflozin exposure-response relationship in Japanese and non-Japanese patients with type 1 diabetes mellitus (T1DM) and investigate if a dose adjustment is required in Japanese patients. MATERIALS AND METHODS: Data from two clinical studies were used to develop a non-linear mixed effects model describing the relationship between dapagliflozin exposure (area under the concentration curve) and response (24-hour urinary glucose excretion [UGE]) in Japanese and non-Japanese patients with T1DM. The effects of patient-level characteristics (covariates; identified using a stepwise procedure) on response was also assessed. Simulations were performed using median-normalized covariate values. RESULTS: Data from 84 patients were included. Average self-monitored blood glucose (SMBG) at day 7, change from baseline in total insulin dose at day 7, and baseline estimated glomerular filtration rate (eGFR) all had a significant effect on 24-hours UGE, with SMBG being the most influential. Dapagliflozin systemic exposure for matching doses and baseline eGFR was similar between Japanese and non-Japanese patients; however, higher SMBG and a greater reduction in total insulin dose was observed in the Japanese population. When the significant covariates were included, the model fit the data well for both populations, and accurately predicted exposure-response in the Japanese and non-Japanese populations, in agreement with the observed data. CONCLUSIONS: There was no difference in dapagliflozin exposure-response in Japanese and non-Japanese patients with T1DM once differences in renal function, glycaemic control and insulin dose reductions between studies were considered. Therefore, no dose adjustment is recommended in Japanese patients with T1DM.
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Pueblo Asiatico , Compuestos de Bencidrilo/administración & dosificación , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Glucósidos/administración & dosificación , Glucosuria/orina , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Adolescente , Adulto , Anciano , Simulación por Computador , Diabetes Mellitus Tipo 1/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Eliminación Renal , Estados Unidos , Adulto JovenRESUMEN
AIMS: To compare the effects of the sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin on estimated (ePV) and measured plasma volume (mPV) and to characterize the effects of dapagliflozin on ePV in a broad population of patients with type 2 diabetes. MATERIALS AND METHODS: The Strauss formula was used to calculate changes in ePV. Change in plasma volume measured with 125 I-human serum albumin (mPV) was compared with change in ePV in 10 patients with type 2 diabetes randomized to dapagliflozin 10 mg/d or placebo. Subsequently, changes in ePV were measured in a pooled database of 13 phase 2b/3 placebo-controlled clinical trials involving 4533 patients with type 2 diabetes who were randomized to dapagliflozin 10 mg daily or matched placebo. RESULTS: The median change in ePV was similar to the median change in mPV (-9.4% and -9.0%) during dapagliflozin treatment. In the pooled analysis of clinical trials, dapagliflozin decreased ePV by 9.6% (95% confidence interval 9.0 to 10.2) compared to placebo after 24 weeks. This effect was consistent in various patient subgroups, including subgroups with or without diuretic use or established cardiovascular disease. CONCLUSIONS: ePV may be used as a proxy to assess changes in plasma volume during dapagliflozin treatment. Dapagliflozin consistently decreased ePV compared to placebo in a broad population of patients with type 2 diabetes.
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Compuestos de Bencidrilo/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/farmacología , Volumen Plasmático/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Anciano , Compuestos de Bencidrilo/uso terapéutico , Femenino , Glucósidos/uso terapéutico , Insuficiencia Cardíaca , Humanos , Masculino , Persona de Mediana Edad , Albúmina Sérica Humana/análisis , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
AIM: To develop a quantitative drug-disease systems model to investigate the paradox that sodium-glucose co-transporter (SGLT)2 is responsible for >80% of proximal tubule glucose reabsorption, yet SGLT2 inhibitor treatment results in only 30% to 50% less reabsorption in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A physiologically based four-compartment model of renal glucose filtration, reabsorption and excretion via SGLT1 and SGLT2 was developed as a system of ordinary differential equations using R/IQRtools. SGLT2 inhibitor pharmacokinetics and pharmacodynamics were estimated from published concentration-time profiles in plasma and urine and from urinary glucose excretion (UGE) in healthy people and people with T2DM. RESULTS: The final model showed that higher renal glucose reabsorption in people with T2DM versus healthy people was associated with 54% and 28% greater transporter capacity for SGLT1 and SGLT2, respectively. Additionally, the analysis showed that UGE is highly dependent on mean plasma glucose and estimated glomerular filtration rate (eGFR) and that their consideration is critical for interpreting clinical UGE findings. CONCLUSIONS: Quantitative drug-disease system modelling revealed mechanistic differences in renal glucose reabsorption and UGE between healthy people and those with T2DM, and clearly showed that SGLT2 inhibition significantly increased glucose available to SGLT1 downstream in the tubule. Importantly, we found that the findings of lower than expected UGE with SGLT2 inhibition are explained by the shift to SGLT1, which recovered additional glucose (~30% of total).
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Diabetes Mellitus Tipo 2 , Glucosuria , Transportador 1 de Sodio-Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Transportador 2 de Sodio-Glucosa/metabolismo , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/orina , Glucosuria/metabolismo , Glucosuria/orina , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Modelos Biológicos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacologíaRESUMEN
The mechanisms of cardiovascular and renal protection observed in clinical trials of sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) are incompletely understood and likely multifactorial, including natriuretic, diuretic, and antihypertensive effects, glomerular pressure reduction, and lowering of plasma and interstitial fluid volume. To quantitatively evaluate the contribution of proposed SGLT2i mechanisms of action on changes in renal hemodynamics and volume status, we coupled a mathematical model of renal function and volume homeostasis with clinical data in healthy subjects administered 10 mg of dapagliflozin once daily. The minimum set of mechanisms necessary to reproduce observed clinical responses (urinary sodium and water excretion, serum creatinine and sodium) was determined, and important unobserved physiological variables (glomerular pressure, blood and interstitial fluid volume) were then simulated. We further simulated the response to SGLT2i in diabetic virtual patients with and without renal impairment. Multiple mechanisms were required to explain the observed response: 1) direct inhibition of sodium and glucose reabsorption through SGLT2, 2) SGLT2-driven inhibition of Na+/H+ exchanger 3 sodium reabsorption, and 3) osmotic diuresis coupled with peripheral sodium storage. The model also showed that the consequences of these mechanisms include lowering of glomerular pressure, reduction of blood and interstitial fluid volume, and mild blood pressure reduction, in agreement with clinical observations. The simulations suggest that these effects are more significant in diabetic patients than healthy subjects and that while glucose excretion may diminish with renal impairment, improvements in glomerular pressure and blood volume are not diminished at lower glomerular filtration rate, suggesting that cardiorenal benefits of SGLT2i may be sustained in renally impaired patients.
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Compuestos de Bencidrilo/uso terapéutico , Sistema Cardiovascular/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Riñón/efectos de los fármacos , Modelos Cardiovasculares , Insuficiencia Renal Crónica/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Transportador 2 de Sodio-Glucosa/metabolismo , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatología , Simulación por Computador , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Diuresis/efectos de los fármacos , Tasa de Filtración Glomerular/efectos de los fármacos , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/efectos de los fármacos , Humanos , Riñón/metabolismo , Riñón/fisiopatología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Reabsorción Renal/efectos de los fármacos , Transportador 1 de Sodio-Glucosa/metabolismo , Resultado del TratamientoRESUMEN
The effect of a sodium glucose cotransporter 2 inhibitor (SGLT2i) in reducing heart failure hospitalization in the EMPA-REG OUTCOMES trial has raised the possibility of using these agents to treat established heart failure. We hypothesize that osmotic diuresis induced by SGLT2 inhibition, a distinctly different diuretic mechanism than that of other diuretic classes, results in greater electrolyte-free water clearance and, ultimately, in greater fluid clearance from the interstitial fluid (IF) space than from the circulation, potentially resulting in congestion relief with minimal impact on blood volume, arterial filling and organ perfusion. We utilize a mathematical model to illustrate that electrolyte-free water clearance results in a greater reduction in IF volume compared to blood volume, and that this difference may be mediated by peripheral sequestration of osmotically inactive sodium. By coupling the model with data on plasma and urinary sodium and water in healthy subjects who received either the SGLT2i dapagliflozin or loop diuretic bumetanide, we predict that dapagliflozin produces a 2-fold greater reduction in IF volume compared to blood volume, while the reduction in IF volume with bumetanide is only 78% of the reduction in blood volume. Heart failure is characterized by excess fluid accumulation, in both the vascular compartment and interstitial space, yet many heart failure patients have arterial underfilling because of low cardiac output, which may be aggravated by conventional diuretic treatment. Thus, we hypothesize that, by reducing IF volume to a greater extent than blood volume, SGLT2 inhibitors might provide better control of congestion without reducing arterial filling and perfusion.
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Compuestos de Bencidrilo/farmacología , Bumetanida/farmacología , Diuréticos/farmacología , Glucósidos/farmacología , Insuficiencia Cardíaca/prevención & control , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Adulto , Compuestos de Bencidrilo/administración & dosificación , Volumen Sanguíneo/efectos de los fármacos , Bumetanida/administración & dosificación , Diuresis/efectos de los fármacos , Combinación de Medicamentos , Interacciones Farmacológicas , Femenino , Glucósidos/administración & dosificación , Insuficiencia Cardíaca/orina , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Concentración Osmolar , Sodio/orina , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Desequilibrio Hidroelectrolítico/fisiopatología , Adulto JovenRESUMEN
This study aimed to quantify the effect of the immediate release (IR) of exenatide, a short-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA), on gastric emptying rate (GER) and the glucose rate of appearance (GluRA), and evaluate the influence of drug characteristics and food-related factors on postprandial plasma glucose (PPG) stabilization under GLP-1RA treatment. A quantitative systems pharmacology (QSP) approach was used, and the proposed model was based on data from published sources including: (1) GLP-1 and exenatide plasma concentration-time profiles; (2) GER estimates under placebo, GLP-1 or exenatide IR dosing; and (3) GluRA measurements upon food intake. According to the model's predictions, the recommended twice-daily 5- and 10-µg exenatide IR treatment is associated with GluRA flattening after morning and evening meals (48%-49%), whereas the midday GluRA peak is affected to a lesser degree (5%-30%) due to lower plasma drug concentrations. This effect was dose-dependent and influenced by food carbohydrate content, but not by the lag time between exenatide injection and meal ingestion. Hence, GER inhibition by exenatide IR represents an important additional mechanism of its effect on PPG.
Asunto(s)
Carbohidratos de la Dieta/metabolismo , Exenatida/uso terapéutico , Vaciamiento Gástrico/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Incretinas/uso terapéutico , Absorción Intestinal/efectos de los fármacos , Modelos Biológicos , Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Digestión/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Liberación de Fármacos , Exenatida/administración & dosificación , Exenatida/sangre , Exenatida/farmacocinética , Péptido 1 Similar al Glucagón/sangre , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Humanos , Hiperglucemia/prevención & control , Hipoglucemia/prevención & control , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/sangre , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Incretinas/administración & dosificación , Incretinas/sangre , Incretinas/farmacocinética , Periodo Posprandial , Biología de SistemasRESUMEN
BACKGROUND: In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial in patients with type 2 diabetes mellitus (T2D) at high risk of cardiovascular (CV) disease, saxagliptin did not increase the risk for major CV adverse events. However, there was an unexpected imbalance in events of hospitalization for heart failure (hHF), one of six components of the secondary CV composite endpoint, with a greater number of events observed with saxagliptin. Here, we examined findings from nonclinical safety and clinical pharmacology studies of saxagliptin with the aim of identifying any potential signals of myocardial injury. METHODS: In vitro and in vivo (rat, dog, monkey) safety pharmacology and toxicology studies evaluating the potential effects of saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, on the CV system are reviewed. In addition, results from saxagliptin clinical studies are discussed: one randomized, 2-period, double-blind, placebo-controlled single-ascending-dose study (up to 100 mg); one randomized, double-blind, placebo-controlled, sequential, multiple-ascending-high-dose study (up to 400 mg/day for 14 days); and one randomized, double-blind, 4-period, 4-treatment, cross-over thorough QTc study (up to 40 mg/day for 4 days) in healthy volunteers; as well as one randomized, placebo-controlled, sequential multiple-ascending-dose study in patients with T2D (up to 50 mg/day for 14 days). RESULTS: Neither saxagliptin nor 5-hydroxy saxagliptin affected ligand binding to receptors and ion channels (e.g. potassium channels) or action potential duration in in vitro studies. In animal toxicology studies, no changes in the cardiac conduction system, blood pressure, heart rate, contractility, heart weight, or heart histopathology were observed. In healthy participants and patients with T2D, there were no findings suggestive of myocyte injury or fluid overload. Serum chemistry abnormalities indicative of cardiac injury, nonspecific muscle damage, or fluid homeostasis changes were infrequent and balanced across treatment groups. There were no QTc changes associated with saxagliptin. No treatment-emergent adverse events suggestive of heart failure or myocardial damage were reported. CONCLUSIONS: The saxagliptin nonclinical and clinical pharmacology programs did not identify evidence of myocardial injury and/or CV harm that may have predicted or may explain the unexpected imbalance in the rate of hHF observed in SAVOR.
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Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipéptidos/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Adamantano/efectos adversos , Adamantano/uso terapéutico , Animales , Cardiotoxinas/efectos adversos , Cardiotoxinas/uso terapéutico , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Dipéptidos/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodosRESUMEN
BMS-663068 is an oral prodrug of the HIV-1 attachment inhibitor BMS-626529, which prevents viral attachment to host CD4(+) T cells by binding to HIV-1 gp120. To guide dose selection for the phase 3 program, pharmacokinetic/pharmacodynamic modeling was performed using data from two phase 2 studies with HIV-1-infected subjects (n = 244). BMS-626529 population pharmacokinetics were described by a two-compartment model with first-order elimination from the central compartment, zero-order release of prodrug from the extended-release formulation into a hypothetical absorption compartment, and first-order absorption into the central compartment. The covariates of BMS-663068 formulation type, lean body mass, baseline CD8(+) T-cell percentage, and ritonavir coadministration were found to be significant contributors to intersubject variability. Exposure-response analyses showed a relationship between the loge-transformed concentration at the end of a dosing interval (Ctau) normalized for the protein binding-adjusted BMS-626529 half-maximal (50%) inhibitory concentration (PBAIC50) and the change in the HIV-1 RNA level from the baseline level after 7 days of BMS-663068 monotherapy. The probability of achieving a decline in HIV-1 RNA level of >0.5 or >1.0 log10 copies/ml as a function of the loge-transformed PBAIC50-adjusted Ctau after 7 days of monotherapy was 99 to 100% and 57 to 73%, respectively, for proposed BMS-663068 doses of 400 mg twice daily (BID), 600 mg BID (not studied in the phase 2b study), 800 mg BID, 600 mg once daily (QD), and 1,200 mg QD. On the basis of a slight advantage in efficacy of BID dosing over QD dosing, similar responses for the 600- and 800-mg BID doses, and prior clinical observations, BMS-663068 at 600 mg BID was predicted to have the optimal benefit-risk profile and selected for further clinical investigation. (The phase 2a proof-of-concept study AI438006 and the phase 2b study AI438011 are registered at ClinicalTrials.gov under numbers NCT01009814 and NCT01384734, respectively.).
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Organofosfatos/uso terapéutico , Piperazinas/uso terapéutico , Triazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Esquema de Medicación , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Concentración 50 Inhibidora , Masculino , Persona de Mediana Edad , Organofosfatos/administración & dosificación , Organofosfatos/farmacocinética , Piperazinas/administración & dosificación , Piperazinas/farmacocinética , Profármacos/administración & dosificación , Profármacos/farmacocinética , Profármacos/uso terapéutico , Triazoles/administración & dosificación , Triazoles/farmacocinéticaRESUMEN
Dapagliflozin (Farxiga), alone, or in the fixed dose combination with metformin (Xigduo), is an orally active, highly selective, reversible inhibitor of sodium-glucose cotransporter type 2 (SGLT2) that is marketed in United States, Europe, and many other countries for the treatment of type 2 diabetes mellitus. Here we report a liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical assay of dapagliflozin in human plasma. A lower limit of quantitation (LLOQ) at 0.2 ng/mL with 50 µL of plasma was obtained, which reflects a 5-fold improvement of the overall assay sensitivity in comparison to the previous most sensitive assay using the same mass spectrometry instrumentation. In this new assay, acetate adduct ions in negative electrospray ionization mode were used as the precursor ions for selective reaction monitoring (SRM) detection. Sample preparation procedures and LC conditions were further developed to enhance the column life span and achieve the separation of dapagliflozin from potential interferences, especially its epimers. The assay also quantifies dapagliflozin's major systemic circulating glucuronide metabolite, BMS-801576, concentrations in human plasma. The assay was successfully transferred to contract research organizations (CROs), validated, and implemented for the sample analysis of pediatric and other critical clinical studies. This assay can be widely used for bioanalytical support of future clinical studies for the newly approved drug Farxiga or any combination therapy containing dapagliflozin.