Bioavailability and bioequivalence

1. DR. FEHMI. M. MUKADAM JR1 DEPARTMENT OF PHARMACOLOGY DR. V.M.G.M.C SOLAPUR.

2. Content: • Bioavailability: • Definition • Measurement • Factors affecting bioavailability: • Pharmaceutical Factors • Pharmacological Factors • Bioequivalence: • Definition • Types of Equivalence: • Chemical Equivalence • Pharmaceutical Equivalence • Therapeutic Equivalence • Clinical Equivalence

3. BIOAVAILABILITY • 100% absorption not possible due to certain factors that affect drug absorption. • Liver- highly saturated with enzymes so it does not allow drug to pass freely without metabolizing certain amount of drug.

4. Bioavailability is never expressed in mg. • It is always expressed as Fraction (F) • Here, 100 mg drug was given orally • 50 mg (unchanged form)reached systemic circulation • Bioavailability = = 0.5 • Thus, bioavailability is fraction of unchanged drug reaching the systemic circulation following administration by any route. BIOAVAILABILITY = Where, 0 < F  1

5. DEFINITION: • Bioavailability is defined as “the rate and the extent to which the active concentration of the drug is available at the desired site of action (or bloodstream)” [as per US Food and Drug Administration]. • BIOAVAILABILITY is an absolute term which requires measurement of both the true rate and total amount (extent) of the drug that reaches the systemic circulation from an administered dosage form. • EQUIVALENCEis a relative termwhich means a comparison of 2 different brand products of the same drug with a set of established standards.

6. Rate of Absorption: • The rate of absorption is determined by: • The site of administration: Fastest to slowest • The drug formulation: Decreasing order

7. Extent (amount) of absorption: • For drug administered i.v- Bioavailability is 100 % • For drugs administered i.m / s.c- Close to 100% • But for drugs administered orally: Bioavailability is < 100%. (due to lack of absorption from the gut).

8. Both rate of absorption and extent of input can influence the clinical effectiveness of a drug. • Blood concentration-time curves, shows that the changes in the rate of absorption and extent of bioavailability can influence both the duration of action and the effectiveness of the same total dose of the drug administered in 3 different formulations.

9. MEASUREMENT OF BIOAVAILABILITY: • To calculate bioavailability: drug is given by oral and i.v route to the same person. • Compare the bioavailability of the active drug in systemic circulation following non-invasive administration with the same drug following intravenous administration % BIOAVAILABILITY (Fab) = x 100

10. From plasma concentration-time curves, thus obtained 3 imp characteristics are noted and compared: simple indicators for the rate of absorption. AUC denotes the total amount of drug absorbed into the circulation during a specified period. • Peak plasma concentration (Cmax) • Time to attain the peak plasma concentration (tmax) • The area under the curve (AUC) of plasma concentration vs time curve (till plasma concentration has fallen to 10% of the peak value. • For the product to be considered bioequivalent- • Cmax , tmax & AUC should be same

11. Methods to calculate AUC: • Planimeter: An instrument for mechanically measuring the area of plane figures. • Cut and Weigh method: To cut out the area under curve on rectilinear graph paper and weigh it on an analytical balance. • Mathematical: Using Trapezoid rule. • Measurement of AUC is a better index of bioavailability for drugs to be given for a longer period because here the total drug absorbed becomes more crucial than the peak concentration achieved/ the time required to achieve the peak concentration.

12. Factors influencing absorption and bioavailability:

13. Pharmaceutical Factors: • On Oral Administration, 2 processes precede the actual absorption process- i) Disintegration & ii) Dissolution

14. Particle Size: • Particle size  Dissolution rate surface area • Particle size • has no consequence on • Freely water-soluble drugs. • No need to reduce the particle size • e.g. PARACETAMOL

15. Crystal Form: • Absorption rate and bioavailability of a drug depends on its crystalline form. e.g. Amorphous chloramphenicol palmitate, Amorphous novobiocin Amorphous forms Dissolves better than the crystalline forms, As no energy is required to break the crystalline lattice  Bioavailability- Increased

16. Salt Form: • A dissolution rate of a particular salt is usually different from that of the parent compound. Tolbutamide & Phenytoin (Free drug) E.g. Tolbutamide Sodium & Phenytoin Sodium (Salt form) BETTER BIOAVAILABILITY THAN

17. Water of Hydration: • Many drugs can associate with water to produce crystalline forms called the hydrates. If water molecules are already present in a crystal structure, the tendency of the crystal to attract additional water and initiate dissolution process is reduced, compared to anhydrous form

18. Degree of Ionisation: i.e. STOMACH i.e. SMALL INTESTINE

19. Nature of Excipients and Adjuvants: • Nature of excipients have tremendous effect on bioavailability of Drugs like- • Phenytoin, Digoxin, Levodopa, warfarin, etc. e.g. PHENYTOIN TOXICITY- In epileptic patients (1968) where in DILANTIN SODIUM CAPSULE- Calcium sulphate was replaced with Lactose.

20. Pharmacological Factors: • Gastric emptying and gastrointestinal motility: • Factors that accelerate gastric emptyingincreases the bioavailability because, the drug is exposed to larger surface area of small intestine early.

21. Gastrointestinal disease: • Pathological factors that affect drug absorption: • In Coeliac disease (malabsorption of fats): Amoxycillin and pivampicillin: show decreased absorption. Cephalexin: show increased absorption. Ampicillin: no change. • InCrohn’s disease (chronic inflammation of ileum): There is a disproportionate absorption of individual components from: cotrimoxazole Absorption of Trimethoprim:decreased. while Sulfamethoxazole: increased. • In Gastroenteritis:decreased absorption of drugs if given orally.

22. Food and other substances: • But both the rate and extentof absorption of certain antibiotics e.g. Rifampicin: is reduced after meals. • Absorption of Tetracycline: reduced if taken with milk or milk products. (forms poorly absorbed complexes with the calcium ions). • Vitamin C: keeps Iron in ferrous form and increases its bioavailability. • Absorption of Anti-fungal drugs (Griseofulvin):enhanced by absorption of drugs with Fatty diet.

23. First-pass effect: • All drugs taken orally, first pass through GIT wall and then through Portal system before reaching systemic circulation. • A drug can be metabolized in the gut wall (e.g. CYP3A4- enzyme system- substrate for P-gp) or in the portal circulation before reaching the systemic circulation. • LIVER > Intestine. • Net result: decreased bioavailability and diminished therapeutic response. • Bioavailability of L-dopa, morphine, nitroglycerin, isosorbide dinitrate and propranolol/labetalol is less, if given orally- due to significant first-pass effect

24. Drug-Drug interaction: • Difference in bioavailability can be due to: drug-drug interactions.

25. Pharmacogenetic factors: • Large differences in bioavailability often exist among humans due to pharmacogenetic reasons. Isoniazid Induced Neurotoxicity

26. Miscellaneous factors: • Route of administration: Parenteral > Rectal > Oral > Topical. • Area of absorbing surface: Drugs better absorbed from small intestine than from the stomach because of the larger surface area of the small intestine. • State of circulation at the site of absorption (in shock- where tissue perfusion gets decreased)

27. BIOEQUIVALENCE Needs Research, Investments, trials  costly • When 2 drugs- Drug A and Drug B are said to be bioequivalent? • E.g., Drug company X- designs a new drug (BRANDED DRUG) Patent for suppose-20 years. (no other company can copy this drug) once patency expires, now any other company can legally copy this drug (GENERIC DRUG) But, needs approval by FDA- (asks for bioequivalence certificate) i.e., if compound produced by A,B… companies is equivalent to compound produced by X. i.e., It has to prove that Amount as well as rate of is similar. • Bioequivalence: 2 pharmaceutically equivalent compound with similar rate and extent of absorption. • Bioequivalence is required for approval of generic drug. • Range: normal acceptable range-  20-25 % No investments  cheap

28. Definition: • EQUIVALENCE is a relative termwhich means a comparison of two different brand products of a same drug with a state of established standards. • If 2 or more similar dosage forms of the same drug reaches the blood circulation at the same relative rate and extent, these are called BIOEQUIVALENT preparation of the generic drugs. • Difference in the bioavailability is usually seen with oral dosage forms, because bioavailability of any drug given i.v- 100%. (i.m & s.c close to 100%). • Difference of < 25% in bioavailability among several drug formulations of one drug will usually have no significant effect on clinical outcome, hence such formulations can be called BIOEQUIVALENT

29. Types of Equivalence: • Chemical Equivalence: If two or more dosage forms of the same drug contain the same labeled quantities of the drug as specified in pharmacopoeia, these are chemical equivalent drugs. 2 Brands of a drug May be chemically equivalent But may not be bioequivalent

30. Pharmaceutical Equivalence:

31. Therapeutic Equivalence: If 2 brand products of 1 drug provide an “identical in vivo pharmacological response” as measured by control of symptoms or a disease and safety profile they can be considered therapeutically Equivalent. They may or may not be Pharmacokinetically equivalent

32. Clinical Equivalence: If one structurally different drug can provide the same clinical response as another mechanically related drug, they exhibit clinical equivalence.

33. References: • Goodman L.S, Goodman & Gilman’s Pharmacological Basics of Therapeutics, 13th edition, New York; New Delhi, Tata McGraw-Hill Education, 2017. • Katzung B.G, Basic and Clinical Pharmacology, 14th edition, New York; New Delhi, Tata McGraw-Hill Education, 2017. • Tripathi K.D., Essentials of Medicine Pharmacology 8th edition, New Delhi, Jaypee Brothers Publications, 2019. • Sharma H.L, Principles of Pharmacology, 3rd edition, New Delhi, Paras Medical Publisher, 2018.

34. THANK YOU