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  2. 2. Bioavailability Objectives of bioavailability Factors effecting bioavailability Measurement of bioavailability Bioequivalence Terms to know in Bioequivalence Types of Bioequivalence studies Acknowledgement 2
  3. 3. 3
  4. 4. Regulatory Definition (21 CFR 320.1(a)): “ Bioavailability- means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action." Or “Bioavailability is defined as rate and extent of absorption of unchanged drug from it’s dosage form and become available at the site of action.” 4
  5. 5. Primary stages of development of a suitable dosage form for new drug entity. Determination of influence of excipients, patient related factors and interaction with other drugs on the efficiency of absorption. To evaluate the absolute systemic availability of active drug substance from a dosage form. Control quality of drug in early stages of development. Develop new formulation for existing drug. 5
  6. 6. Systemic availability the amount that reaches systemic circulation is simply known as availability. Absolute bioavailability of a drug product may be comparing the respective bioavailabilites after an oral and iv bolus injection. Relative bioavailability is defined as a ratios of bioavilabilities of a drug product and reference standard. 6
  7. 7. Absolute bioavailability Relative bioavailability 7
  8. 8. Route Bioavailability (%) Characteristics Intravenous (IV) 100 (by definition) Most rapid onset Intramuscular (IM) 75 to ≤ 100 Large volumes often possible; may be painful Subcutaneous (SC) 75 to ≤ 100 Smaller volumes than IM; may be painful Oral (PO) 5 to < 100 Most convenient; first pass effects may be significant Rectal (PR) 30 to < 100 Less first-pass effects than oral Inhalation 5 to < 100 Often very rapid onset Trans-dermal 80 to ≤ 100 Usually very slow absorption; used for lack of first-pass effects; prolonged duration of action.
  9. 9. 9 Three major factors that effecting bioavailability:- 1. Pharmaceutical factors 2. Patient related factors 3. Routes of administration.
  10. 10. Bioavailability Pharmaceutical Factors Physicochemical Factors Pharmaco- Technical Factors PatientRelated Factors Route Of Administration 1 0
  11. 11. 1.Pharmaceutical factors:  Physicochemical properties of the drug. 1. Particle size 2. Crystalline structure 3. Salt form  Pharmaco - Technical Factors or Formulation and manufacturing variables. 1.Disintegration and dissolution time 2.Pharmaceutical ingredients 3.Special coatings 4.Nature and type of dosage form 0
  12. 12. 2. Patient related factors:  Physiologic factors. 1.Variations in pH of GI fluids 2.Gastric emptying rate 3. Intestinal motility 4. Pre-systemic 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 0
  13. 13. The methods available are:- Pharmacokinetic (Indirect) Method Pharmacodynamic (Direct) Method. Selection of method depends upon :- Nature of The Study Nature of Dosage Form Analytical Method Development. 10
  14. 14. 11 Bio availability Indirect methods Plasma data T maxT max C max AUC Urinary data dx u/dt AUC Xu (T u ) Max Direct methods Acute pharmacolog ical response Clinical response (d Xu/dt ) Max
  15. 15. Widely used and based on assumption that Pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Plasma Level- Time Studies: Most common type of human bioavailability studies. Based on the assumption that there is a direct relationship between the concentration of drug in blood or plasma and the concentration of drug at the site of action. Following the administration of a single dose of a medication, blood samples are drawn at specific time intervals and analyzed for drug content. 0
  16. 16. A profile is constructed showing the concentration of drug in blood at the specific times the samples were taken. Bioavailability (the rate and extent of drug absorption) is generally assessed by the determination of following three parameters. They are.. 1. Cmax (Peak plasma concentration) 2. Tmax (time of peak) 3. AUC (Area under curve) 10
  17. 17. Plasma Drug Concentration Vs Time Graph 17
  18. 18. Cmax - Maximum plasma concentration. 1.The concentration of drug at therapeutic response is elicited. 2.Increase with increase in dose and with an increase in absorption. 3.Expressed in terms of μg/ml or mg/ml. Tmax-Time to reach maximum concentration 1.Indicates rate of absorption. 2.It decrease as the rate of absorption increases. 3.Expressed in terms of hours or minutes. AUC - Area under thecurve. 1.Indicates the extent of drug absorption from a dosage form. 2.The fraction of dose that reaches the systemic circulation. 18
  19. 19.  MEC: The minimum plasma concentration of the drug required to achieve a given pharmacological or therapeutic response.  MSC: Plasma concentration of the drug beyond which adverse effects are likely to happen.  THERAPEUTIC RANGE: The range of plasma drug concentration in which the desired response is achieved yet avoiding adverse effect. The aim is clinical practice is to maintain plasma drug concentration within the therapeutic range.  ONSET OF ACTION: On set of action is the time required to achieve the minimum effective plasma concentration following administration of drug formulation.19
  20. 20.  DURATION OF ACTION- Duration of action of the therapeutic effect of the drug is defined as the time period during which the plasma concentration of the drug exceeds the minimum effective level.  INTENSITY OF ACTION- In general, the difference between the peak plasma concentration and the minimum effective plasma concentration provides a relative measure of the intensity of the therapeutic response of the drug. 20
  21. 21. The extent of bioavailability is calculated from equation : For single dose study: 21
  22. 22. Urinary Excretion Studies: Urinary excretion of unchanged drug is directly proportional to plasma concentration of drug. Thus, even if a drug is excreted to some extent (at least 10 to 20%) in the urine, bioavailability can be determined. eg: Thiazide diuretics, Sulphonamides. Method is useful when there is lack of sufficiently sensitive analytical technique to measure drug concentration. Noninvasive method, so better patient compliance. 0
  23. 23. Rate of urinary excretion of drug versus time plot 23
  24. 24. Maximum urinary excretion rate • Its value increases as rate and/or extent of absorption increases. • It is obtained from peak of plot between rate of urinary excretion data versus time of urine collection period. Time for maximum excretion rate • It is the maximum time required to reach maximum excretion rate. • Its value decreases as absorption rate increases. • Analogues of tmax of plasma level data. Cumulative amount of drug excreted (X)u∞ • It is the drug excreted in urine till the drug level fallszero. Related to AUC of plasma level data. • It increases as the extent of absorption increases. 24
  25. 25. The extent of bioavailability is calculated from equation: 25
  26. 26. Sr. No Plasma data Urinary data 1. Maximum plasma concentration C max Maximum urinary excretion rate 2. Time to maximum concentration T max Time to maximum excretion rate 3. Area under the curve AUC Cumulative amount of drug excreted 26
  27. 27. 27
  28. 28. Acute pharmacological response When bioavailability measurement by pharmacokinetic method is difficult, an acute pharmacologic effect are taken into consideration. Dose response curve Can be determined by construction of Pharmacological effect Vs Timecurve. E.g.: pupil diameter, heart rate or BP can be useful as an index of drug Bioavailability. Disadvantage: • It tends to be more variable. • Observed response may be due to an active metabolite whose concentration is not proportional to concentration of parent drug. 18
  29. 29. Clinical response / Therapeutic response •Best method Clinical response of the drug for which it is intended to be used is measured. •Based on clinical response to the drug formulation given to the patients E.g.: for anti-inflammatory drugs, reduction in inflammation is determined Drawbacks: The major drawbacks of this method is that quantitation of observed response is too improper to allow for reasonable assessment of relative bioavailability between two dosage forms of the same drug. 18
  30. 30. 19
  31. 31. Bioequivalence When the drug from two or more similar dosage form reaches the general circulation at the same relative rate and extent then the dosage forms are termed as Bioequivalent. Statistical significant differences are observed in the bioavailability of two or more drug products, termed as Bio-inequivalence. 20
  32. 32. 1. A comparison of the bioavailability of two or more drug products. 2. Two products or formulations containing the same active ingredient are bioequivalent if their rates and extents of absorption are the same. 3. Bioequivalence may be demonstrated through in vivo or in vitro test methods, comparative clinical trials, or pharmacodynamic studies. 20
  33. 33. 33 0 10 20 30 40 50 60 70 80 90 0 10 20 30 Concentration(ng/mL) Time(hours) Test/Generic Reference/Brand
  34. 34. Bioequivalence: IR Products Reference Test Pharmaceutical Equivalent Products Possible Differences Drug particle size, .. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Documented Bioequivalence = Therapeutic Equivalence (Note: Generally, same dissolution spec.) Normal healthy subjects Crossover design Overnight fast Glass of water 90% CI within 80-125% of Ref. (Cmax & AUC)
  35. 35. When significant changes are made in the manufacture of the marketed formulation. When a new generic formulation is tested against the innovator's marketed product. Comparison of availability of drug substance from different dosage forms. when changes in formulation have occurred after an innovator product has been approved. Comparison of availability's of same dosage formproduced by different manufactures. 21
  36. 36. Equivalence Chemical equivalence Clinical equivalence Pharmaceutical Equivalence Bioequivalence Therapeutic equivalence Comparable Dosage Form 36
  37. 37. Equivalence may be defined in several ways: Chemical equivalence: If two or more dosage forms of same drug contain same labeled quantities specified in pharmacopoeia. Eg : Dilantin and Eptoin chemically equivalent as they contain same quantity of Phenytoin on chemical assay. Bioequivalence: The drug substance in two or more identical dosage forms, reaches the systemic circulation at the same relative rate and extent i.e. their plasma concentration-time profiles will be identical without significant statistical differences.
  38. 38. Pharmaceutical equivalents: Drug products in identical dosage forms that contain same active ingredient(s), i.e , the same salt or ester, are of the same dosage form, use the same route of administration, and are identical in strength or concentration. Eg : Chlordiazepoxide hydrochloride,5mg capsules. Pharmaceutical equivalent drug products are: Same in : •Active ingredient and it’s quantity •Dosage form •Standards like strength, quality , purity and identity. •Disintegration time •Dissolution rates Differ in: •Shape •Release mechanisms •Packing •Excipients(including colours , flavours , preservatives) •labeling
  39. 39. Pharmaceutical alternatives: •Drug product that contain the same therapeutic moiety but as different salts, esters or complexes. Eg: Tetracyclin phosphate or Tetracyclin hydrochloride equivalent to 250mg. Therapeutic equivalents: •Drug products consider to be therapeutic equivalence only if they are pharmaceutical equivalence and if they can be expected to have a same clinical effect and safety profile when administered to patient specified in the labeling. •FDA classifies as therapeutically equivalent those products that meet the fallowing general criteria: 1)They approved as safe and effective. 2)They are pharmaceutically equivalents. 3)They are bioequivalence. 4)They are adequately labeled . 5)They are manufactured in compliance with current GMP regulations.
  40. 40. Therapeutic alternatives: •Drug products containing different active ingredients that are indicated for the same therapeutic or clinical objectives. Eg: 1. Ibuprofen is given instead of Aspirin. 2. Cimetidine instead of Ranitidine. Therapeutic substitution: •The process of dispensing a therapeutic alternative in place of the prescribed drug product. Eg: 1. Ampicillin is dispensed instead of Amoxicillin. 2. Ibuprofen is dispensed instead of Naproxen.
  41. 41. Bioequivalence studies In vivo Oral immediate release Non oral immediate release Modified release with systemic action In vitro Clinical studies 41
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  43. 43. 46