STUDY OF ANTIDIABETIC DRUG GLYBURIDE

BIOAVAILABILITY AND BIOEQUIVALENCE STUDY OF ANTIDIABETIC DRUG GLYBURIDE IN

HEALTHY HUMAN VOLUNTEERS

Under the guidance ofUnder the guidance ofDr. A.T. BAPUJI,Dr. A.T. BAPUJI, M.Pharm Ph.D., M.Pharm Ph.D., APL- RC-1, Bachupally, R.R.District, APL- RC-1, Bachupally, R.R.District,

Hyderabad.Hyderabad.

Internal guideInternal guide B. Kishore Kumar ReddyB. Kishore Kumar Reddy Pharmacology department,Pharmacology department, S K University.S K University.

Submitted by

K. SUJATHA(Reg. No.95501035)

Pharmacology.

CONTENTS

INTRODUCTION

Bioavailability

Bioequivalance

DRUG SPECIFIC REVIEW

AIM AND OBJECTIVE OF THE STUDY

MATERIALS AND METHOD

PHARMACOKINETIC ANALYSIS

INTRODUCTION

In recent years, generic drug products, which are those manufactured by

various companies other than the innovator, have become very popular.

For the approval of a generic drug product, the FDA usually Require

ANDA Submission.

The generic drug companies can provide the evidence of bioequivalence

between the generic drug products and the innovator Products in ANDA.

Bioavailability is a measurement of the extent to which a drug reaches the

systemic circulation.

BIOAVAILABILITY: The bioavailability of a drug is defined as the rate

and extent to which the active ingredient or therapeutic moiety is absorbed

and becomes available at the site of action.

BIOEQUIVALANCE

DEFINITION: “The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study."

Three situations have thus been defined in which bioequivalence studies are required:

When the proposed dosage form is different from that used in pivotal clinical trails,

When significant changes are made in the manufacture of the marketed formulation and,

When a new generic formulation is tested against the innovator marketed product

DIABETES MELLITUSDiabetes is a group of metabolic diseases in which a person

has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced.

TWO MAJOR TYPES OF DIABETES:Type 1 diabetesType 2 diabetesDiabetes mellitus type 1: (Insulin dependent diabetes or

IDDM, or juvenile diabetes) is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas (type1A) or idiopathic (type1B).The subsequent lack of insulin leads to increased blood and urine glucose.

Diabetes mellitus type 2

TREATMENT OF TYPE 2 DMDiet Management:Try to avoid fat particularly saturated fat and use less butter, cheese and eat

fewer fatty meals.Use less salt as high intake can rise blood pressureAlcohol contain carbohydrates and,if consumed in excess, may cause

hyperglycemia.

DrugTherapy-oral hypoglycemic agents

SULFONYLUREAS: 1st&2nd GenerationsMEGLITINIDES: Repaglinide,NeteglinideBIGUANIDES: Metformin,FenforminTHIAZOLIDINEDIONS: Rosiglitazone,Pioglitazoneα-GLYCOSIDASE INHIBITORS:Acarbose.Miglitol

DRUG SPECIFIC REVIEW Glyburide: (sulfonylurea) The molecular weight is 493.99

Clinical pharmacology:

High affinity receptors for sufonylureas are present on the kATP channels in

β-cell plasma membranes, and the binding of sulfoylureas paralles their

potency in stimulating insulin release. The drugs reduce the k+ permeability

of β-cells by blocking kATP channnels, causing depolarisation, ca2+ entry and

insulin secretion.

.

Pharmacokinetics

Absorption with in one hour, Tmax is 4 hrs,Half life is 10hrs.

Distribution:It is extensively bound to serum proteins.

Metabolism:Major metabolite is trns hydroxy derivative

Excretion:It excreted as metabolites in bile and urine.

Contraindications: Hypersensitivity,type1DM people

Dosage: No fixed dose. Starting dose is 2.5 to 5 mg daily,

Maintanance dose is 1.25 to 20 mg daily Maximum dose is 20

mg.

AIM OF THE STUDY

To compare the rate and extent of absorption of Glyburide

5mg tablets of Aurobindo Pharma Pvt.Ltd (INDIA), as test

with Diabea 5mg tablets, (containing glyburide 5mg) of

Sanofi-Avenis,(USA) of in healthy, adult, male, human

subjects under fasting conditions

MATERIALS AND STUDY DESIGN

Materials: Test Formulation(t): Glyburide 5mg tablets of Aurobindo

pharma Pvt.Ltd (INDIA).

Reference(r) is Diabeta 5mg tablets ,(each containing Glyburide 5mg) of

Sanofi -Aventis(USA).

STUDY DESIGN:

An open label, randomized, two-treatment, two sequence, two period,

single dose crossover, comparative oral Bioavailability study of Glyburide

5mg tablets,Comparing with Diabeta 5mg tablet manufactured of Sanofi

Aventis,USA, in healthy, adult, male, human subjects under fasting

conditions.

Pre–study laboratory evaluation parameters

CLINICAL CHEMISTRY HEMATOLOGY SEROLOGY

Random blood sugar Total W.B.C HIV-1

Blood urea nitrogen(BUN) Total R.B.C HIV-2

creatinine Hemoglobin HbsAg

Total bilirubin PCV HCV

SGOT, Neutrophils

SGPT lymphocytes

blood cholesterol Mixed cells

Total proteins platelets

Sodium ESR(1hr)

potassium

STUDY DESIGN SCHEME

GroupsNo.of study participants(N)=14

Perod 1 Wash out period

Period 2

Group 1 7 Treatment A

7days

Treatment B

Group 2 7 Treatment B

7days

Treatment A

Subject

No

Sequence Period - I Period - II

1 TR T R

2 RT R T

3 TR T R

4 RT R T

5 TR T R

6 RT R T

7 RT R T

8 TR T R

9 RT R T

10 RT R T

11 TR T R

12 TR T R

randamisation scheme for the study

DIETARY PLAN:

After check-in, all the subjects will receive standard diet of

approximately 2600 - 2800 calories per day. The subjects will

receive a standard meal about 4.00, 8.00, 12.00, 24.00 hours

after dosing in each period SAMPLING SCHEDULES:

The venous blood samples (6 ml each) will be withdrawn at

pre-dose (before dosing, in the morning of the day of dosing)

00.00hours and at 00.50, 01.00, 02.00, 03.00, 03.50, 04.00,

04.50, 05.00, 06.00, 08.00, 10.00, 12.00, 16.00, 20.00, 24.00,

36.00 and 48.00 hours after dosing.

SAMPLING PROCEDURE AND HANDLING OF SAMPLES:

Blood samples will be collected through an indwelling cannula

placed in a forearm vein using disposable syringe

BLOOD LOSS:

Approximately 258 ml [including about 216 ml of blood for

Pharmacokinetic analysis, about 10 ml of blood for clinical

laboratory tests for each pre study screening and about 10 ml of

blood for post study safety assessment and 22 ml as total volume

discarded before each sampling except for pre-dose] total blood

will be drawn from each subject, for both the period.

PHARMACOKINETIC PARAMETERS

After collecting the blood samples we have to measure these parameters to

compare the bioequvalance between the generic and innovator products.

Tmax: Time of maximum measured plasma concentration.

Cmax: Maximum measured plasma concentration following each treatment.

AUC0–t: The area under the plasma concentration versus time curve from time zero to

the last measurable concentration, as calculated by the linear trapezoidal method.

AUC0– : AUC0- is calculated as the sum of the AUC0-t plus the ratio of the last

measurable concentration to the elimination rate constant.

Kel: Apparent first order elimination or terminal rate constant calculated from semi

log plot of the plasma concentration versus time curve.

T1/2: Time required for the plasma drug concentration to decrease to one half.

REFERENCES CPMP (Committee for Proprietary Medicinal Products), 2001, Note for Guidance on

Bioavailability and Bioequivalence. Retrieved from www.emea.europa.eu/pdfs /human/

ewp/140198en.pdf , accessed on 20 Feb. 2008

Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Cotran, Ramzi S. ; Robbins, Stanley L.

(2005). Robbins and Cotran Pathologic Basis of Disease (7th ed.). Philadelphia, Pa.:

Saunders. pp. 1194–1195.

Welch, B. J.; Zib, I. (October 2004). "Case Study: Diabetic Ketoacidosis in Type 2 Diabetes:

"Look Under the Sheets"". Clinical Diabetes 22 (4): 19

Risérus U, Willett WC, Hu FB (January 2009). "Dietary fats and prevention of type 2

diabetes". Progress in Lipid Research 48 (1): 44–51.  

Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA et al. (2010).

"Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a

mechanism for enhanced IL-1β in type 2 diabetes.". Nat Immunol 11 (10): 897–904.

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