Model-Based Meta-Analysis of the HbA1c Lowering Effect Of PF-04971729, a Sodium Glucose Co-Transporter-2 Inhibitor (SGLT2i), In Comparison to Other SGLT2i And Anti-Diabetic Agents (ADA)

PF-04971729 is a potent, selective SGLT2i in development for treatment of type 2 diabetes mellitus (T2DM). Since there is growing recognition of the need for comparative effectiveness of various ADA, a model was developed to quantify time course of dose vs HbA1c response of PF-04971729 relative to other ADA including SGLT2i, DPP4 inhibitors (DPP4i), GLP-1 […]

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Model-Based Meta-Analysis of the Effect on Body Weight of PF-04971729, a Sodium Glucose Co-Transporter-2 Inhibitor (SGLT2i), in Comparison to other SGLT2i and Anti-Diabetic Agents (ADA)

PF-04971729 is a potent, selective SGLT2i in development for treatment of type 2 diabetes mellitus (T2DM). Since there is growing recognition of the need for comparative effectiveness of various ADA, a model was developed to quantify the time course of dose vs body weight change for PF-04971729 relative to other ADA including SGLT2i, DPP4 inhibitors […]

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Using Model-based Meta-analysis to Improve Decision-making in Drug Development

Making the right choices in drug development often means the difference between getting a new medication to patients and it ending up in the scrap heap of failed programs. There is a surfeit of publicly available information on approved drugs as well as those currently in development. How can sponsors turn clinical trial data into understanding that helps chart the course for investigational drugs?

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Pharmacometric Approaches to Guide Dose Selection of the Novel GPR40 Agonist TAK-875 in Subjects With Type 2 Diabetes Mellitus

The G-protein-coupled receptor 40 agonist (GPR40) TAK-875 is being developed as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Pharmacometric approaches such as model-based exposure-response and meta-analyses were applied to (i) characterize exposure/dose-efficacy responses of TAK-875, (ii) characterize the time course of glycosylated hemoglobin A1c (HbA1c) […]

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Safe Dosing for Organ Impairment

A model-enhanced view into exposure levels supported high-confidence dose selection and opened the way for study in patients with organ impairment. A small virtual pharmaceutical company achieved clinical proof-of-concept for a new formulation of an approved drug, which it hoped would overcome a contraindication to use the drug in a key patient population. In early-phase […]

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Modeling and Simulation Supports Competitve Product Profile Assessment

Modeling strategy provided sponsor timely and compelling support for positive efficacy signal of in-licensing candidate, helping to secure $23 Million financing round and advance compound to Phase IIB. A specialty pharmaceutical company was seeking to provide rapid, quantitative support to fund its in-licensing strategy for an oral Type 2 anti-diabetic agent. Limited data from a […]

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Population Pharmacokinetic Model for a Novel Oral Hypoglycemic Formed In Vivo: Comparing the Use of Active Metabolite Data Alone Versus Using Data of Upstream and Downstream Metabolites

The purpose of this analysis was to develop a population pharmacokinetic model for CS-917, an oral hypoglycemic prodrug, and its 3 metabolites. The population pharmacokinetic model was used to predict exposure of the active moiety R-125338 and thus to identify potential CS-917 dosage reduction criteria.

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The Use of Biosimulation in the Design of a Novel Multilevel Weight Loss Maintenance Program for Overweight Children

Weight loss outcomes achieved through conventional behavior change interventions are prone to deterioration over time. Basic learning laboratory studies in the area of behavioral extinction and renewal and multilevel models of weight control offer clues as to why newly acquired weight loss skills are prone to relapse.

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CYP2D6 is primarily responsible for the metabolism of clomiphene.

Clomiphene is a first line treatment for anovulation, a common cause of infertility. Response to clomiphene is variable and unpredictable. Tamoxifen is structurally related to clomiphene, and also shows considerable variation in response. CYP2D6 and CYP3A4 are major contributors to the metabolism of tamoxifen. The aim of the present work was to define the role […]

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Study reanalysis using a mechanism-based pharmacokinetic/pharmacodynamic model of pramlintide in subjects with type 1 diabetes.

This report describes a pharmacokinetic/pharmacodynamic model for pramlintide, an amylinomimetic, in type 1 diabetes mellitus (T1DM). Plasma glucose and drug concentrations were obtained following bolus and 2-h intravenous infusions of pramlintide at three dose levels or placebo in 25 T1DM subjects during the postprandial period in a crossover study. The original clinical data were reanalyzed […]

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Population pharmacokinetic analysis of dutogliptin, a selective dipeptidyl peptidase-4 inhibitor

Dutogliptin is a selective dipeptidyl peptidase-4 inhibitor shown to be efficacious and safe in patients with type 2 diabetes mellitus (T2DM). Population pharmacokinetic (PK) analysis of dutogliptin was performed based on data collected in 561 healthy subjects and patients with T2DM enrolled in Phase I and II studies to assess sources of variability and support […]

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3D-QSAR studies and molecular docking on [5-(4-amino-1H-benzoimidazol-2-yl)-furan-2-yl]-phosphonic acid derivatives as fructose-1,6-biphophatase inhibitors

Fructose-1,6-biphophatase has been regarded as a novel therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). 3D-QSAR and docking studies were performed on a series of [5-(4-amino-1H-benzoimidazol-2-yl)-furan-2-yl]-phosphonic acid derivatives as fructose-1,6-biphophatase inhibitors. The CoMFA and CoMSIA models using thirty-seven molecules in the training set gave rcv2 values of 0.614 and 0.598, r2 values […]

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