project about pharma data and related research

Project K

1. BIOAVAILABILITY AND BIO EQUIVALENCE STUDY OF FENOFIBRATE SR 10 mg CAPSULES IN HEALTHY HUMAN VOLUNTEERS BY PRASANNA RAMAKRISHNA.G (Y11MPH0644) Under the guidance of Mr. G.KIRAN ( Asst . professor), A.M.Reddy memorial College of Pharmacy, Narasaraopet, Guntur . 1

2. INTRODUCTION OBJECTIVE DRUG PROFILE MATERIALS AND METHODS RESULTS CONCLUSION REFERENCES CONTENTS : 2

3. The concept of Bioavailability and Bioequivalence plays an important role in drug research and development, especially in generic-drug industry. The cost of healthcare has been escalating globally during the last two decades, and this has prompted efforts in most countries to reduce those costs. As a result, generic drug equivalents of brand-name drugs (innovator drugs) are introduced. The national average savings through the use of generic drugs from 1997–2000 was approximately 9 billion dollars or 11% of total prescription costs. At the same time, generic drugs have captured more than 65% of the global pharmaceutical market. Average prescription spending in the United States topped 286 billion in 2007, prompting calls for greater generic drug use to reduce costs without sacrificing quality. INTRODUCTION 3

4. US FDA was authorized to approve generic drug products under the “Drug Price Competition and Patent Term Restoration Act” which was passed by the U.S Congress in 1984. The FDA publishes a list of brand name drugs whose patent protection has expired in “Approved Drug Products with Therapeutic Equivalence Evaluations” commonly known as the Orange Book. Once patent exclusivity of a brand-name drug expires, an application for generic drug approval can be submitted to the US Food and Drug Administration (FDA). A generic drug is required to demonstrate bioequivalence to the brand-name drug. 4

5. BIOAVAILABILITY: T he rate and extent at which the drug is available at the site of action after its absorption in to blood (systemic circulation). BIOEQUIVALENCE: I t is a relative term which denotes that the drug substance in two or more identical dosage forms, reaches the systemic circulation at the same relative rate and to the same relative extent i.e. their plasma concentration-time profiles will be identical without significant statistical differences. 5

6. IMPORTANCE OF BIOAVAILABILITY AND BIO EQUIVALENCE Development of new formulations of the existing drugs. Concern about lowering health care costs is resulted in tremendous increase in use of generic products. To demonstrate the therapeutic equivalence of a generic product and the reference product. To support certain post-approval changes in approved products. 6

7. SCHEMATIC DIAGRAM OF EVENTS IN BA/BE STUDIES 7

8. DESIGN Generally the study design and number of studies (single dose and/or multiple-dose and/or fasting and/or fed) depend on the RLD or reference product, physico -chemical properties of the drug, its pharmacokinetic properties(geographical, food habits, and metabolic variations), and proportionality in composition with justification along with respective regulatory guidance and specifications. 8

9. As recommended by the US FDA (1992), in most bioequivalence trials, a “test” formulation is compared with the standard / innovator “reference” formulation, in a group of normal, healthy subjects (18-45 yr), each of whom receive both the treatments alternately, in a crossover fashion (two-period, two-treatment crossover design), with the two phases of treatment separated by a “washout period” of generally a week’s duration, but may be longer (a minimum time equivalent to 5 half-lives) if the elimination half-life of the drug is very long. The treatment is assigned to each subject, randomly, but an equal number of subjects receive each treatment in each phase. Thus, in case of two treatments A and B, one group gets the treatment in the order AB and the second group in the reverse order BA. This is done to avoid the occurrence of possible sequence or period effects. A similar allocation is done in case of a three-treatment crossover design (three-period, three-treatment crossover design). 9

10. DESIGNS USED IN BA & BE STUDIES: Randomization: Allocation of treatment to the subjects without selection bias . Replication: Treatment is applied to more than one experimental unit (subject) to obtain more reliable estimates than is possible from a single observation. Types Of Replication Designs For Two Medications: Four-sequence and two-period design (Balaam’s design)   Two-sequence and four-period design Four-sequence and four-period design         Two-sequence and three-period design           Crossover design for three medications (Williams’ design) Crossover design for four medications (Williams’ design) 10

11. T he present study is designed to compare a generic product of single Oral- dose Fenofibrate SR 10 mg capsules manufactured by RA chem pharma ltd., FDF division with the standard formulation S ecalip ® SR 10 mg capsules (containing fenofibrate 10 mg), S olvay pharmaceuticals, Turkey in healthy, adult, human subjects under fed conditions. NEED OF STUDY 11

12. DRUG PROFILE : Name : Fenofibrate Molecular Weight : 360.83 Category : L ipid lowering drugs Appearance : w hite solid Solubility : i nsoluble in water Dosage : A vailable in strengths of 40mg, 120mg, 250mg capsules , administration orally. Storage : 25°C (77°F) 12

13. MECHANISM OF ACTION: F enofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating “Lipoprotein Lipase” and reducing production of Apo protein c-iii (an inhibitor of lipoprotein lipase activity). T he resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. T hese larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. 13

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15. PHARMACOKINETICS Absorption: W ell absorbed from gastrointestinal tract. Maximal peak plasma concentration ( C max ) of Fenofibrate occurring 2- 3 hrs. post dose. Distribution: T he apparent volume of distribution on averages about 16-40 %. It is highly bound to proteins in human serum. Metabolism: M etabolized primarily by esterase's. No unchanged fenofibrate is detected in plasma. Elimination half life is about 2-3 hrs. Excretion: 60% of the dose is excreted in urine. about 25% was excreted in feces. 15

16. ADVERSE EFFECTS : N ausea Abdominal pain Rhinitis Back pain Constipation Headache CONTRAINDICATIONS : R enal dysfunction Patients with liver disease including primary biliary cirrhosis Hypersensitivity Contraindicated in nursing mothers Patients with gallbladder disease 16

17. MATERIALS: Weighing Balance with printer Sonicator Digital P H meter Centrifuge Nitrogen Evaporator LCMS/MS-3000 17

18. TEST PRODUCT : F enofibrate 10 mg SR capsule (containing 10 mg of fenofibrate) manufactured by capsules manufactured by R a chem pharma ltd., FDF division, I ndia . REFERENCE PRODUCT : S ecalip ® SR 10 mg capsules (containing fenofibrate 10 mg), S olvay pharmaceuticals, Turkey. SOURCES OF DRUGS 18

19. EXCLUSION CRITERIA : Contraindications or hypersensitivity to Fenofibrate . History of presence of any disease , alcoholism , smoking , or asthma . Difficulty in donating the blood or swallowing the capsules . Systolic B.P less than 100mm Hg or more than 140mmHg . Diastolic B.P less than 70mm Hg or more than 90mm Hg . HIV positive . Major illness during three months before screening. INCLUSION CRITERIA: Human male subjects aged from 18 to 55 years . Subjects within the BMI range 18.5 to 24.9 kg/m² . Subjects with vital sings in normal range . Subjects with normal medical and surgical history and normal functioning of all the systems . Normal functioning of lymph nodes and other parts like head , neck, ears, throat and eyes . Subjects with normal laboratory values. 19

20. HOUSING: The subjects were housed in the clinical facility at Clinical research and bio-sciences clinical department from at least 12 hours prior to drug administration until 24 hours post dose in each study period . DIET: All subjects were instructed to abstain from any xanthine-containing food or beverages (tea, coffee, chocolates, soft drinks etc.), grapefruit, or alcoholic products at least 48 hours prior to dosing till the end of sampling in each period and drinking water were restricted from 1hr pre-dose and 2hr post-dose. 20

21. DOSE ADMINISTRATION: Subjects were instructed not to chew or crush the capsule but consume as a whole . Administration of investigational products was done when the subjects are in standing posture and instructed to remain in sitting position for 2 hrs. after dosing . If subjects were ambulatory but they were advised to avoid severe physical exertion. 21

22. SAMPLING SCHEDULE : In each study period, 22 blood samples were collected from each subject as per the following schedule. The first blood sample (1 x 10 ml) was collected within 1 hour prior to dosing. The post-dose blood samples (1x 5 ml each) was collected at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50,1.75, 2.00, 2.25, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00,12.00, 16.00 and 24.00 hours after dosing. The total volume collected per subject in this study was not exceeded 271 ml. 22

23. BLOOD SAMPLING Blood samples were collected through an indwelling cannula placed in a forearm vein . After the collection of blood sample at each time point, sample was transferred to sample collection tubes containing K 2 -EDTA as anticoagulant . Blood samples were collected within + 2 minutes of specified sampling time during housing period. WASHOUT PERIOD There was a washout period of at least 14 days between each dosing period. 23

24. PROCESSING AND STORAGE: After collection, blood samples were centrifuged at a temperature of 4±2°C, approximately 4000 rpm for 10 minutes . As soon as possible, the plasma obtained was separated and transferred into two different polypropylene tube / RIA vials. Each tube was labeled. All samples were stored at a temperature of -20°C . At the end of the study, samples were shipped to bio analytical department for analysis. 24

25. BIOANALYTICAL PROCEDURES: Validated LCMS/MS method was employed for the estimation of Fenofibrate in plasma STATISTICAL TOOLS: Statistical analysis was performed with Pharmacokinetic variables like C max , T max , AUC 0-t , AUC 0-inf , K el , t 1/2 were calculated using pk -solver. The Least Square Mean values, T/R ratio values are reported . 25

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27. RESULTS N = 14 Parameter AUC 0-t AUC 0-  C max T max T½ K el Test (A) Mean 29931.02 35380.98 3687.772 2.446429 8.5478 0.086489 Co-efficient Variation 29.72081     31.24514       34.22818     42.64154     26.29709     26.56409   Reference (B) Mean 28695.69     33178.87       3717.76     2.553571     7.6861     0.09209   Co-efficient Variation 31.75464     31.63944       25.74872     46.9017     15.1634     14.85843   Least square Mean Test (A) 10.26274 10.42843 8.195501 - - - Reference (B) 10.22098 10.36681 8.150893 - - - 90% Confidence Interval for Test(A) Lower Limit 102.2270076 104.2912617 101.7874722 - - - Upper Limit 106.3434326 108.4622972 107.4117814 - - - 27

28. MEAN GRAPH OF FENOFIBRATE 28

29. The bioavailability and bioequivalence study of fenofibrate 10 mg SR capsules was conducted on 14 healthy, human, male volunteers. The pharmacokinetic parameters (auc0-t and c max ) are with in the acceptable limits of bioequivalence 80 – 125%. Hence , it is concluded that the test drug of fenofibrate 10mg SR capsules is bioequivalent with reference drug of S ecalip ® SR 10 mg capsules (containing fenofibrate 10 mg) . CONCLUSION 29

30. References http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2782076/ . Access date 17/07/2013. Costas H. Kefalas, MD, FACG, FASGE, AGAF, Arthur A. Ciociola , PhD and the FDA-Related Matters Committee of the American College of Gastroenterology. The FDA’s Generic-Drug Approval Process: Similarities to and Differences From Brand-Name Drugs. 2011; 106:1018–1021. Brahmankar DM, Jaiswal SB. Biopharmaceutics and Pharmacokinetics A Treatise: Ed: Jain MK, Vallabh prakashan , Second Edition; 2009; p: 315 - 319. Shaik Mastan , Thirunagari Bhavya Latha , Sathe Ajay. The basic regulatory considerations and prospects for conducting bioavailability/bioequivalence (BA/BE) studies – an overview. Comparative Effectiveness Research 2011:1 1–25. Madan PL. Bioavailability and Bioequivalence, the Underlying Concepts, US Pharm , 1992; 17: H10-H30. www.rxlist.com . 30

31. THANK YOU 31