BIOAVAILABILITY AND BIOEQUIVALENCE

STUDY OF ANTIDIABETIC DRUG GLYBURIDE IN

HEALTHY HUMAN VOLUNTEERS
Under the guidance of
Dr. A.T. BAPUJI, M.Pharm Ph.D.,
APL- RC-1, Bachupally, R.R.District,
Hyderabad.
Internal guide
B. Kishore Kumar Reddy
Pharmacology department,
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

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

INTRODUCTION

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.

DEFINITION:
The absence of a significant difference in the rate
BIOEQUIVALANCE
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 MELLITUS
Diabetes 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 diabetes
Type 2 diabetes
Diabetes 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 DM
Diet 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 pressure
Alcohol contain carbohydrates and,if consumed in excess, may cause
hyperglycemia.
DrugTherapy-oral hypoglycemic agents
SULFONYLUREAS: 1st&2nd Generations
MEGLITINIDES: Repaglinide,Neteglinide
BIGUANIDES: Metformin,Fenformin
THIAZOLIDINEDIONS: Rosiglitazone,Pioglitazone
-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 k ATP channels in
-cell plasma membranes, and the binding of sulfoylureas paralles their
potency in stimulating insulin release. The drugs reduce the k + permeability
of -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.

Prestudy 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

Groups
Group 1

No.of study Perod 1

participants
(N)=14
7

Wash Period 2
out
period

Treatment A

Treatment

7days
Group 2

Treatment B

Treatment A
7days

Subject

randamisation scheme for the study

Sequence

Period - I

Period - II

TR

RT

TR

RT

TR

RT

RT

TR

RT

10

RT

11

TR

12

TR

No

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.
AUC0t: 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 AUC 0-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. 11941195.
Welch, B. J.; Zib, I. (October 2004). "Case Study: Diabetic Ketoacidosis in Type 2 Diabetes:

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

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

diabetes". Progress in Lipid Research 48 (1): 4451.

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-1 in type 2 diabetes.". Nat Immunol 11 (10): 897904.

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