Population Pharmacodynamic Dose-Response Analysis of Serum Potassium Following Dosing with Sodium Zirconium Cyclosilicate.

Background: Sodium zirconium cyclosilicate (SZC) is an approved oral treatment for hyperkalemia that selectively binds potassium (K) in the gastrointestinal tract and removes K from the body through increased fecal excretion. Here, we describe the population pharmacodynamic (PopPD) response of serum K concentration in patients with hyperkalemia who are treated with SZC, estimate the impact of patients' intrinsic and extrinsic factors, and compare predicted serum K responses between 5 g alternate daily (QOD) and 2.5 g once daily (QD) maintenance doses.

Potassium homeostasis and therapeutic intervention with sodium zirconium cyclosilicate: A model-informed drug development case study.

Potassium (K ) is the main intracellular cation in the body. Elevated K levels (hyperkalemia) increase the risk of life-threatening arrhythmias and sudden cardiac death. However, the details of K homeostasis and the effects of orally administered K binders, such as sodium zirconium cyclosilicate (SZC), on K redistribution and excretion in patients remain incompletely understood.

Effectiveness of dapagliflozin as an insulin adjunct in type 1 diabetes: a semi-mechanistic exposure-response model.

Dapagliflozin-induced improvement of glycemic control in patients with inadequately controlled type 1 diabetes (T1D) is complicated by the delicate balance between blood glucose and exogenous insulin. In this work, we developed a semi-mechanistic population exposure-response model using pooled patient-level data to characterize the joint effect of dapagliflozin and insulin on average daily glucose concentrations and glycated hemoglobin (HbA1c) levels in patients with T1D. A non-linear mixed-effects model was developed in Monolix (Lixoft, France) and R software (R Project, www.

Dapagliflozin pharmacokinetics is similar between patients with heart failure with reduced ejection fraction and patients with type 2 diabetes mellitus.

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.

A mechanistic modeling platform of SGLT2 inhibition: Implications for type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by abnormally high blood glucose concentrations due to dysfunction of the insulin-producing beta-cells in the pancreas. Dapagliflozin, an inhibitor of renal glucose reabsorption, has the potential to improve often suboptimal glycemic control in patients with T1DM through insulin-independent mechanisms and to partially mitigate the adverse effects associated with long-term insulin administration. In this work, we have adapted a systems pharmacology model of type 2 diabetes mellitus to describe the T1DM condition and characterize the effect of dapagliflozin on short- and long-term glycemic markers under various treatment scenarios.

Evaluation of the Pharmacokinetics of Dapagliflozin in Patients With Chronic Kidney Disease With or Without Type 2 Diabetes Mellitus.

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.

Dapagliflozin Pharmacokinetics Is Similar in Adults With Type 1 and Type 2 Diabetes Mellitus.

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.

Predicted Cardiac Functional Responses to Renal Actions of SGLT2i in the DAPACARD Trial Population: A Mathematical Modeling Analysis.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to reduce the risk of worsening heart failure (HF) in subjects with HF and a reduced ejection fraction (HFrEF) in multiple clinical trials. The DAPACARD clinical trial was conducted to examine the effects of dapagliflozin on cardiac substrate uptake, myocardial efficiency, and myocardial contractile work in subjects with type 2 diabetes mellitus. As a complement to the clinical study, a mechanistic mathematical model of cardiorenal physiology was used to quantify the influence of established natriuretic/diuretic effects of SGLT2i on cardiac function (myocardial efficiency and global longitudinal strain).

Cardiovascular and renal safety of metformin in patients with diabetes and moderate or severe chronic kidney disease: Observations from the EXSCEL and SAVOR-TIMI 53 cardiovascular outcomes trials.

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/1.73m 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.

A model-based approach to investigating the relationship between glucose-insulin dynamics and dapagliflozin treatment effect in patients with type 2 diabetes.

Aims: To develop a quantitative systems pharmacology model to describe the effect of dapagliflozin (a sodium-glucose co-transporter-2 [SGLT2] inhibitor) on glucose-insulin dynamics in type 2 diabetes mellitus (T2DM) patients, and to identify key determinants of treatment-mediated glycated haemoglobin (HbA1c) reduction.

Materials And Methods: Glycaemic control during dapagliflozin treatment was mechanistically characterized by integrating components representing dapagliflozin pharmacokinetics (PK), glucose-insulin homeostasis, renal glucose reabsorption, and HbA1c formation. The model was developed using PK variables, glucose, plasma insulin, and urinary glucose excretion (UGE) from a phase IIa dapagliflozin trial in patients with T2DM (NCT00162305).

Predicted Cardiac Hemodynamic Consequences of the Renal Actions of SGLT2i in the DAPA-HF Study Population: A Mathematical Modeling Analysis.

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study demonstrated that dapagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), reduced heart failure hospitalization and cardiovascular death in patients with heart failure with reduced ejection fraction (HF-rEF), with and without type 2 diabetes mellitus. Multiple potential mechanisms have been proposed to explain this benefit, which may be multifactorial. This study aimed to quantify the contribution of the known natriuretic/diuretic effects of SGLT2is to changes in cardiac hemodynamics, remodeling, and fluid homeostasis in the setting of HF-rEF.

Effect of once-weekly exenatide on estimated glomerular filtration rate slope depends on baseline renal risk: A post hoc analysis of the EXSCEL trial.

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.

Renal Effects of Dapagliflozin in People with and without Diabetes with Moderate or Severe Renal Dysfunction: Prospective Modeling of an Ongoing Clinical Trial.

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.

Differentiating the Sodium-Glucose Cotransporter 1 Inhibition Capacity of Canagliflozin vs. Dapagliflozin and Empagliflozin Using Quantitative Systems Pharmacology Modeling.

The aim of this research was to differentiate dapagliflozin, empagliflozin, and canagliflozin based on their capacity to inhibit sodium-glucose cotransporter (SGLT) 1 and 2 in patients with type 2 diabetes using a previously developed quantitative systems pharmacology model of renal glucose filtration, reabsorption, and excretion. The analysis was based on pooled, mean study-level data on 24-hour urinary glucose excretion, average daily plasma glucose, and estimated glomerular filtration rate collected from phase I and II clinical trials of SGLT2 inhibitors. Variations in filtered glucose across clinical studies were shown to drive the apparent differences in the glucosuria dose-response relationships among the gliflozins.

Prediction and validation of exenatide risk marker effects on progression of renal disease: Insights from EXSCEL.

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).

Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial.

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.

Comparison of the urinary glucose excretion contributions of SGLT2 and SGLT1: A quantitative systems pharmacology analysis in healthy individuals and patients with type 2 diabetes treated with SGLT2 inhibitors.

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.

Reduction of Cardiovascular Risk and Improved Estimated Glomerular Filtration Rate by SGLT2 Inhibitors, Including Dapagliflozin, Is Consistent Across the Class: An Analysis of the Placebo Arm of EXSCEL.

Objective: The sodium-glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin and canagliflozin reduce the incidence of major adverse cardiovascular events (MACE), all-cause mortality (ACM), and renal events in cardiovascular outcomes trials, with observational real-world evidence suggesting class effect benefits that include dapagliflozin. We examined the placebo arm of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) to determine whether the effects of drop-in open-label dapagliflozin on MACE, ACM, and estimated glomerular filtration rate (eGFR) were consistent with the SGLT2i class as a whole.

Research Design And Methods: SGLT2i drop-in therapy occurred in 10.

Urinary glucose excretion after dapagliflozin treatment: An exposure-response modelling comparison between Japanese and non-Japanese patients diagnosed with type 1 diabetes mellitus.

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.

Exenatide effects on gastric emptying rate and the glucose rate of appearance in plasma: A quantitative assessment using an integrative systems pharmacology model.

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.

Novel orally swallowable IntelliCap(®) device to quantify regional drug absorption in human GI tract using diltiazem as model drug.

Typically, colonic absorption of a drug is mandatory for a sustained release formulation to hold the drug's plasma level for more than 12 or 24 h above the minimum therapeutic plasma concentration (efficacy). According to Drugs@FDA, only 7.4% of the oral drugs are extended release forms probably showing colonic absorption.

Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation.

The human cardiac sodium channel (hNav1.5, encoded by the SCN5A gene) is critical for action potential generation and propagation in the heart. Drug-induced sodium channel inhibition decreases the rate of cardiomyocyte depolarization and consequently conduction velocity and can have serious implications for cardiac safety.