A Phase I, Single Centre, Single-blind, Randomised, Placebo-controlled, Parallel-group Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral AZD7687 After Administration of Single and Multiple Ascending Doses in Healthy Male Japanese Subjects

This is a study in Japanese healthy volunteers to determine the safety and tolerability of the compound AZD7687. It will also assess how the body handles the drug and how it responds to the drug following single dose followed by multiple dosing over 7 days.

Start Date01 Nov 2010

Sponsor / Collaborator

AstraZeneca PLC

NCT01119352 / CompletedPhase 1

A Phase 1, Single Centre, Single-Blind, Randomised, Placebo-controlled, Parallel-group Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral AZD7687 After Administration of Multiple Ascending Doses in Overweight to Obese But Otherwise Healthy Male Subjects

The aim of the study is to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD7687 following multiple ascending dose administrations in in overweight to obese but otherwise healthy male subjects

Start Date01 Apr 2010

Sponsor / Collaborator

AstraZeneca PLC

NCT01046357 / CompletedPhase 1

A Randomized, Blind, Placebo-controlled, Single-centre Phase I Study in Healthy Volunteers to Assess the Safety, Tolerability and Pharmacokinetics of AZD7687 After Single Ascending Oral Doses

This is a Phase I, first time in human, randomised, blinded, placebo-controlled, single ascending dose study in healthy male volunteers conducted at a single centre. The effect of food on the pharmacokinetics of AZD7687 will also be studied.
The study will consist of two parts, a dose escalation part and a food interaction part. The two parts will be run in parallel. In total, 64 healthy volunteers divided in 8 different panels (8 volunteers per cohort) will be exposed to single doses during the dose escalation. Each subject will receive dose only once, except for the volunteers included in the dose steps repeated for food interaction.

Start Date01 Nov 2009

Sponsor / Collaborator

AstraZeneca PLC

100 Clinical Results associated with AZD-7687

100 Translational Medicine associated with AZD-7687

100 Patents (Medical) associated with AZD-7687

Literatures (Medical) associated with AZD-7687

01 Apr 2019·Pharmacology Research & PerspectivesQ4 · MEDICINE

Evolving data analysis of an Oral Lipid Tolerance Test toward the standard for the Oral Glucose Tolerance Test: Cross species modeling effects of AZD7687 on plasma triacylglycerol

Q4 · MEDICINE

ArticleOA

Author: Nilsson, Catarina ; Morentin Gutierrez, Pablo ; Birtles, Sue ; Yates, James

AbstractWe have developed a novel mechanistic pharmacokinetic‐pharmacodynamic (PK/PD) model to describe the time course of plasma triglyceride (TAG) after Oral Lipid Tolerance Test (OLTT) and the effects of AZD7687, an inhibitor of diacylglycerol acyltransferase 1 (DGAT1), in humans, rats, and mice. Pharmacokinetic and plasma TAG data were obtained both in animals and in two phase I OLTT studies. In the PK/PD model, the introduction of exogenous TAG is represented by a first order process. The endogenous production and removal of TAG from plasma are described with a turnover model. AZD7687 inhibits the contribution of exogenous TAG into circulation. One or two compartment models with first order absorption was used to describe the PK of AZD7687 for the different species. Nonlinear mixed effect modeling was used to fit the model to the data. The effects of AZD7687 on the plasma TAG time course during an OLTT as well as interindividual variability were well described by the model in all three species. Meal fat content or data from single vs repeated dosing did not affect model parameter estimates. Body mass index was found to be a significant covariate on the plasma TAG baseline. The system parameters of the model will facilitate analysis for other compounds and provide tools to bring the standard of OLTT data analysis closer to the analyses of Oral Glucose Tolerance Test data maximizing knowledge gain.

01 Apr 2015·Toxicologic PathologyQ4 · MEDICINE

Pharmacological Inhibition of DGAT1 Induces Sebaceous Gland Atrophy in Mouse and Dog Skin While Overt Alopecia Is Restricted to the Mouse

Q4 · MEDICINE

Article

Author: Lees, David ; Jones, Huw Bowen ; Floettmann, Eike ; Seeliger, Frank

Diacylglycerol O-acyltransferase 1 (DGAT1) plays an important role in synthesizing lipids, and inhibitors of DGAT1 have been investigated as potential treatments for diabetes and metabolic diseases. DGAT1 knockout (−/−) mice are resistant to obesity, have increased sensitivity to insulin, and exhibit sebaceous gland atrophy and alopecia. Prolonged pharmacological inhibition of DGAT1 with AZD7687 in mice results in the same skin phenotype, including sebaceous gland atrophy and alopecia, as seen in the skin of DGAT1 (−/−) mice. AZD7687-mediated effects on the skin were dose- and time-dependent and reversible. They occurred only at substantial levels of continuous DGAT1 inhibition. Prolonged treatment of dogs with AZD7687 also resulted in sebaceous gland atrophy but did not result in the more adverse skin changes of hair loss and skin lesions. Our findings highlight a significant risk of generating the same lesions that were seen in mouse skin during clinical development of DGAT1 inhibitors in humans and also reveal a species difference in the effects on the skin, indicating that the mouse may be an especially sensitive species. Therefore, although human therapeutic doses may not have the same influence on skin morphology as seen in mice, monitoring of skin changes will be essential in clinical trials with DGAT1 inhibitors.

01 Apr 2014·Diabetes, Obesity and MetabolismQ2 · MEDICINE

Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial

Q2 · MEDICINE

Article

Author: Himmelmann, A. ; Mårtensson, G. ; AL‐Shurbaji, A. ; Löfgren, L. ; Denison, H. ; Tornqvist, H. ; Knutsson, M. ; Nilsson, C. ; Eriksson, J. W.

AbstractAimInhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo‐controlled, phase 1 study in 62 overweight or obese men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor.MethodsMultiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 h after a standardized 45% fat meal. Glucagon‐like peptide‐1 (GLP‐1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying.ResultsDose‐dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP‐1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at the end of treatment. With AZD7687 doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea.ConclusionsAltered lipid handling and hormone secretion in the gut were demonstrated during 1‐week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.

100 Deals associated with AZD-7687

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Phase 1	GB	AstraZeneca PLC	01 Nov 2010
Obesity	Phase 1	GB	AstraZeneca PLC	01 Apr 2010

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