Bioavailability and Bioequivalence General concepts and overview

1. Bioavailability and BioequivalenceGeneral concepts and overview

2. WHAT IS IT??? WHY IS IT??? HOW IS IT??? REGULATION VERSUS PHARMACEUTICAL COMP.

5. Generic Drug product: Definition • Same active ingredient (s) • Same strength • Same dosage form • Same route of administration • Same indications

7. Original Drug NDA Requirements Chemistry Manufacturing Controls Labeling Testing Animal Studies Clinical Studies (Bioavailability) Generic Drug ANDA Requirements Chemistry Manufacturing Controls Labeling Testing Bioequivalence Study (In Vivo, In vitro) NDA vs. ANDA Review Process Note: Generic drug applications are termed "abbreviated" because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.  Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the origina; drug).

8. FDA Definitions Used in Bioequivalence Determinations

9. FDA Determinations of Bioequivalence Main Terms • Pharmaceutical equivalents • Pharmaceutical alternatives • Therapeutic equivalents • Bioavailability • Bioequivalence Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.

10. Pharmaceutical Equivalents • Drug products are considered pharmaceutical equivalents if they contain the same active ingredient(s), have the same dosage form and route of administration, and are identical in strength or concentration • Equivalent products contain the same amount of ingredient in the same dosage form but may differ in characteristics, such as shape, release mechanisms, and packaging Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm. Accessed September 29, 2003.

11. Pharmaceutical Alternatives • Drug products are considered pharmaceutical alternatives if they contain the same therapeutic moiety, are different salts, esters, or complexes of the same moiety, are different dosage forms, or are different strengths • tetracycline hydrochloride, 250mg capsules vs. tetracycline phosphate complex, 250mg capsules; quinidine sulfate, 200mg tablets vs. quinidine sulfate, 200mg capsules • Other pharmaceutical alternatives • Different dosage forms and strengths within a single product line by a single manufacturer • Extended-release formulations when compared with immediate- or standard-release formulations Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.

12. Therapeutic Equivalents • Drug products are considered therapeutic equivalents if they are all of the following • Pharmaceutical equivalents • Bioequivalent • Approved as safe and effective • Adequately labeled • Manufactured in compliance with current Good Manufacturing Practice regulations • Therapeutic equivalents are expected to have the same clinical effect and safety profile Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.

13. Pharmacokinetics conc. vs time Conc.(mg/L) 0.0 0 25 Time (h) Bioavailability (quantifies ABSORPTION = ?, Reasons for poor F) • The extent and rate at which its active moiety is delivered from pharmaceutical form and becomes available in the systemic circulation

14. Why do we care about BIOAVAILABILITY? The “true dose” is not the drug swallowed; BUT is the drug available to exert its effect. • 􀂄 Dissolution • 􀂄 Absorption • 􀂄 Survive metabolism May have a drug with very low bioavailability • 􀂄 Dosage form or drug may not dissolve readily • 􀂄 Drug may not be readily pass across biological membranes (i.e. be absorbed) • 􀂄 Drug may be extensively metabolized during absorption process (first-pass, gut wall, liver) Important component of overall variability • 􀂄 Variable bioavailability may produce variable exposure

17. Rate versus Extent of Absorption Extent of absorption is reflected by AUC Rate of absorption, ka, is reflected by Tmax Both Rate and Extent of absorption affect Cmax Leads to 4 possible relative scenarios: • 􀂄 (R) Rapid, (E) Complete Absorption yields a short Tmax, high Cmax, high AUC • 􀂄 (R) Rapid, (E) incomplete absorption yields a short Tmax, low Cmax, low AUC • 􀂄 (R) Slow, (E) complete absorption yields a long Tmax, high Cmax, high AUC • 􀂄 (R) Slow, (E) incomplete absorption yields a long Tmax, low Cmax, low AUC

20. FACTORS INFLUENCING BIOAVAILABILITY: Three distinct factors are involved to influencing bioavailability. These are: .Pharmaceutical factors: • physicochemical properties of the drug. 1. Particle size 2. Crystalline structure 3. Salt form • Formulation and manufacturing variables. 1.Disintegration and dissolution time 2.Pharmaceutical ingredients 3.Special coatings 4.Nature and type of dosage form

21. 2. Patient related factors: • Physiologic factors. 1.Variations in pH of GI fluids 2.Gastric emptying rate 3. Intestinal motility 4. Presystemic and first-pass metabolism 5. Age, sex 6. Disease states • Interactions with other substances. 1. Food 2. Fluid volume 3. Other drugs 3. Route of administration: 1.Parentral administration 2.Oral administration 3.Rectal administration 4.Topical administration

22. Bioequivalence • A comparison of the bioavailability of two or more • drug products. • Two products or formulations containing the same • active ingredient are bioequivalent if their rates • and extents of absorption are the same • Bioequivalence may be demonstrated through in vivo or in vitro test methods, comparative clinical trials, or pharmacodynamic studies Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.

23. Bioequivalence

24. In VIVO SUPAC-MR IVIVC Regulatory Bioequivalence: An Overview “Self-evident” - Biowaivers granted Condition- excipients do not alter absorption (historical data) Solutions Suspensions Chewable, etc. Conventional Tablets Capsules MR Products Pre-1962 DESI Drugs: In Vivo evaluation for “bio-problem” drugs (TI, PK, P-Chem) Post-1962 Drugs: Generally In Vivo - some exceptions (IVIVC..) SUPAC-IR (1995) Dissolution-IR BCS (pre-/post approval)

25. Bioequivalence: IR Products Pharmaceutical Equivalent Products Reference Test Possible Differences Drug particle size, .. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Normal healthy subjects Crossover design Overnight fast Glass of water 90% CI within 80-125% of Ref. (Cmax & AUC) Documented Bioequivalence = Therapeutic Equivalence (Note: Generally, same dissolution spec.) Ajaz Hussain, FDA

26. FDA Methods to Determine Bioequivalence • Generic drug manufacturers must demonstrate that a drug is bioequivalent to a reference drug product • In order of FDA preference, methods used to define bioequivalence • Pharmacokinetic studies • Pharmacodynamic studies • Comparative clinical trials • In vitro studies Food and Drug Administration. Code of Federal Regulations. Title 21, Part 320: Bioavailability and Bioequivalence Requirements. Section 320.24. 2003. Available at: http://www.accessdata.fda.gov. Accessed September 29, 2003.

27. Pharmacokinetic StudiesKey Measurements Study Compound Reference Compound • AUC • Area under the concentration- time curve • Cmax • Maximum concentration • A difference of greater than 20% in Cmax or the AUC represents a significant difference between the study and reference compounds • Tmax • Time to maximum concentration Cmax Concentration AUC Tmax Time Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.

28. Comparative Pharmacodynamic Studies • Not recommended when: • active ingredient is absorbed into the systemic circulation • pharmacokinetic study can be conducted • Local action / no systemic absorption • eg. : Topical Corticosteroid Hanoi, 2006-19-01

29. Comparative Clinical Studies • Pharmacokinetic profile not possible • Lack of suitable pharmacodynamic endpoint • eg . : (Nasal suspensions) Hanoi, 2006-19-01

30. Study Designs • Single-dose, two-way crossover design - Single-dose, parallel design • Multiple-dose studies( in case of : • Drugs too potent/toxic Extended/modified release products

32. Crossover vs. Parallel Designs • Crossover design preferred • Intra-subject comparison • Lower variability • Generally fewer subjects required • Parallel design may be useful • Drug with very long half-life • Crossover design not practical Hanoi, 2006-19-01

33. Disadv. of cross over design • The main problem with the cross over design is : The carry over effect………!?

34. Fasted vs. Fed Designs • Fasted study design preferred • Minimize variability not attributable to formulation • Better able to detect formulation differences Hanoi, 2006-19-01

35. Fed Study Designs may be employed when: • Significant gastrointestinal (GI) disturbance caused by fasted administration • Product labeling restricts administration to fed state Hanoi, 2006-19-01

36. When equivalence studies are NOT necessary (Biowaivers) • Aqueous parenteral solutions • Solutions for oral use ( syrups, elixirs, tinctures & other soluble forms but not suspensions) • Pdrs for reconstitution as a solution • Otic or ophthalmic aqueous solutions • Topical aqueous solutions • Aqueous nebulizing inhalations or nasal sprays

37. B. For some products bioequivalence may be demonstrated by evidence obtained in vitro instead of in vivo data: • The drug product is in the same dosage form, but in a different strength, and is proportionally similar in its active and inactive ingredients to another product by the same manufacturer that was found to be bioequivalent.

38. For high potency drug substances, the same inactive ingredients are used for all strengths, and the change in any strength is obtained by altering the amount of the active ingredients and one or more of the inactive ingerdients are within the limits defined by the SUPAC guidances (up to level II).

39. Waiver of Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System(B.C.S)

40. BCS Classifications According to the BCS, drug substances are classified as follows: • Class I - High Permeability, High Solubility • Class II - High Permeability, Low Solubility • Class III - Low Permeability, High Solubility • Class IV - Low Permeability, Low Solubility

41. Solubility • A drug substance is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1 - 7.5 (WHO , pH: 1.2 – 6.8)

42. Permeability • A drug substance is considered to be highly permeable when the extent of absorption in humans is determined to be 90% or more of an administered dose ( WHO, 85% ).

43. Conditions for BCS Bio-waivers Firms can request waivers of in vivo testing for Class 1 drug substances Drug products must meet these criteria: • Immediate-release solid oral dosage forms • Highly soluble, highly permeable drug substance • Rapid in vitro dissolution Note: Waivers not applicable for narrow therapeutic range therapeutic range (Digoxin, Lithium, phenytoin, warfarin) drugs

44. A drug product is considered to be RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of < 900 ml buffer solutions.

45. BCS Class I: Dissolution • USP Apparatus I (100 rpm) or II (50 rpm) • Three media • 0.1 N HCl or SGF USP without enzymes 0.1 N HCl or SGF USP without enzymes • pH 4.5 buffer pH 4.5 buffer • pH 6.8 buffer or SIF USP without enzymes • NLT 85% dissolves within 30 minutes • Similarity factor (f2) for test (T) v. reference (R) profile comparisons should > 50