Effect of Co-administration of Metformin and Daclatasvir on the Pharmacokinetis and Pharmacodynamics of Metformin

Study Overview
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Brief Summary
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A Randomized,Two-period, Crossover Study to Determine the Possibility of Drug-drug Interaction After Co-administration of Metformin and Daclatasvir Where Twenty Eligible Adult Subjects Will be Randomized to Receive Either Metformin Only and/or Metformin Co-administered With Daclatasvir to measure primary outcomes including pharmacokinetics parameters as: Maximum drug concentration in plasma(Cmax), Area under the Plasma concentration Versus Time Curve from time 0 to 12 hours(AUC0-12), Clearance(CL)

Detailed Description
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Study Design: A randomized, one-way, single blinded, two-period, crossover study in adult human healthy egyptian volunteers Methodology: period (I): Group A:10 volunteers will receive 500 mg Metformin twice daily on day 1-4 then 1000mg metformin twice on day 5-7 GroupB:10 volunteers will receive 500 mg Metformin twice daily + Daclatasvir (DCV) 60 mg once daily on day 1-4 then 1000mg metformin twice daily+DCV 60 mg once daily on day 5-7 period (II): Group A:10 volunteers will receive 500 mg Metformin twice daily + Daclatasvir (DCV) 60 mg once daily on day 1-4 then 1000mg metformin twice daily+DCV 60 mg once daily on day 5-7 Group B:10 volunteers will receive 500 mg Metformin twice daily on day 1-4 then 1000mg metformin twice daily on day 5-7 All drug administration will be followed by 240 ml of water after at least 10 hours fasting prior to administration. The two treatment periods will be separated by a one week washout period Blood Sampling will be collected at a pre-dosing and at 0.25, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12 hours Urine samples will be collected for metformin analysis from 0 to 12 hours after drug administration. A 75 g Oral glucose tolerance test(OGTT) will be carried out by ingestion of 75g glucose in 240ml water 2-hours post dosing and blood samples for determining glucose concentration during OGTTs were collected immediately before and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, and 3 hours after glucose ingestion. Blood samples will be collected from each volunteer prior to drug administration (blank) at the predetermined sampling intervals after drug administration in ethylene diamine tetra-acetic acid(kEDTA) containing tubes. These samples will be centrifuged and the plasma harvested and stored at -80°C until assay.

Official Title
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Effect of Co-administration of Metformin and Daclatasvir on the Pharmacokinetics and Pharmacodynamics of Metformin

Conditions
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Diabetes Mellitus, Type 2, Hepatitis C, Drug Interactions

Intervention / Treatment
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* Drug: Metformin
* Drug: Daclatasvir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is at least 18-55 years at screening. Subject has a Body Mass Index of 18 to 35 kg/m2. Subject are non smokers or moderate smokers(not more than 10 cigarettes per day) Subjects is willing to participate and give their final written consent prior to the commencement of the study procedures Subject is in good age-appropriate health condition as established by medical history, physical examination, and results of biochemistry, hematology and urine analysis testing within 4 weeks prior to study. Subject has a normal blood pressure and pulse rate, according to the reference normal ranges. Exclusion Criteria: Treatment with any known enzyme-inducing/inhibiting agents prior to the start of the study and throughout the study. Subjects who have taken any medication two weeks preceding of the trial starting date. Documented history of sensitivity/idiosyncrasy to medicinal products or excipients. Any prior surgery of the gastrointestinal tract that may interfere with drug absorption. Gastrointestinal diseases. Renal diseases. Cardiovascular diseases specially transient ischemic attacks and cardiac dysrhythmia . Pancreatic disease including diabetes. Hepatic diseases as hepatic failure, cirrhosis, galactose intolerance, fructose intolerance, glycogen storage diseases Hematological disease or pulmonary disease Abnormal laboratory values. Subjects who have donated blood or who have been involved in a drug study within 6 weeks preceding the start of the study. Positive HIV test. History of or current abuse of drugs, alcohol or solvents. Endocrine disorders as Pheochromocytoma, Addison disease, glucagon deficiency, carcinomas, extrahepatic tumors Autoimmune disorders as Graves disease Central nervous system (CNS) disorders

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Twenty Eligible Adult Subjects Will be Randomized Equally into two Groups: A and B To Receive Either: Group (A):10 subjects will receive 500 mg Metformin twice daily on day 1-4 then 1000mg metformin twice on day 5-7 Group (B):10 subjects will receive 500 mg co-administered daily with Daclatasvir 60 mg once daily on day 1-4 then 1000mg Metformin co-administered twice daily with Daclatasvir 60 mg once daily on day 5-7
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metformin<br>Subjects administered Metformin 500mg(Glucophage tablets) twice daily till day(4) then Metformin 1000mg twice daily till day(7) | Drug: Metformin<br>* Metformin is used primarly in treatment of diabetes type II<br>|
| Experimental: Metformin and Daclatasvir<br>Subjects Coadministered Metformin 500mg(Glucophage tablets) twice daily and Daclatasvir 60mg tablets once daily till day (4) then Metformin 1000mg twice daily and Daclatasvir 60mg tablets once daily till Day(7) | Drug: Metformin<br>* Metformin is used primarly in treatment of diabetes type II<br>Drug: Daclatasvir<br>* Daclatsvir is a direct acting antiviral drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (AUC0→12) | Area under the plasma concentration-time curve measured in (nanogram(ng).hr/ml) | From first sampling interval(time zero) up to 12 hours | 
| Area under the plasma concentration-time curve from time 0 to infinity (AUC0→∞) | Area under the plasma concentration-time curve from time 0 to infinity measured in(ng.hr/ml) | From first sampling interval up to infinity | 
| Area under the plasma concentration-time curve from time 0 to tau(AUC0→tau) | Area under the plasma concentration-time curve from time 0 to tau measured in(ng.hr/ml) | From first sampling interval up to dosing interval(Tau) | 
| Maximum drug concentration in plasma at steady state(Cpss) | Maximum drug concentration in plasma at steady state measured in (ng/ml) | Time corresponding to maximum drug concentration in plasma at steady state | 
| Half life( t½) of drug in plasma | Half life of drug measured in Hours(hr) | Up to 12 hours | 
| Mean residence time of drug(MRT) | Mean residence time of drug in plasma measured in (hr) | From first sampling interval up to 12 hours | 
| steady state Clearance of drug(CLss) | steady state Clearance of drug measured in (ml/min) | From first sampling interval up to 12 hours | 
| Renal Clearance of drug(CLr) | Renal Clearance of drug measured in (ml/min) | From first sampling interval up to 12 hours | 
| Cumulative amount of drug eliminated in urine (Ae) | Cumulative amount of drug eliminated in urine measured in (microgram(ug)/ml) | From first sampling interval up to 12 hours | 
| Maximum excretion rate (Urate max) | Maximum excretion rate for the drug measured in (milligram(mg)/hr) | From first sampling interval up to 12 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Glucose(BG) levels | Blood glucose levels measured in (mg/dl) | up to 3 hours | 
| Area under the BG-time curve(AUG)0-3hr | Area under the BG-time curve measured in (mg.hr/dl) | up to 3 hours | 
| Maximum Glucose concentration(Gmax) | Maximum Glucose concentration measured in (mg/dl) | up to 3 hours |