STUDY OF ANTIDIABETIC DRUG GLYBURIDE
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Transcript of 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.
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.