Bioavailability and Bioequivalence        Anas Bahnassi PhD RPh
Lecture ObjectivesUpon the completion of this lecture the student should be able to:• Define terms bioavailability, absolu...
Bioavailability                          Definitions    The relative amount of an                      The rate and extent...
Pharmaceutical                                                  Therapeutic            or Chemical                        ...
Bioequivalence                                                    Compare                                                 ...
Bioavailability Absolute                                       Relative                                                Com...
imAnas Bahnassi PhD 2011        7
Absolute       Bioavailability     ()                           ( )                                F=              ()     ...
Relative         Bioavailability  ()                                    ( )          F=                   ×               ...
()                                                         F=                              ×                              ...
Excipients                                                                   Particle size                     Formulation...
The First Pass Effect   The fraction, f, of orally administered drug thatsuccessfully passes through gut lumen and gut wal...
Determination of the area under the    plasma concentration–time curve from       intravenous bolus administration        ...
Determination of the area under the    plasma concentration–time curve from         extravascular administration          ...
CmaxAssessing Rate ofAbsorption means   comparing:                                         tmax                           ...
Bioavailability TestingAdminister Drug to                                  Minimum 12                           For Relati...
Bioavailability Testing1. Check the criteria for bioavailability testing.2. Compare bioavailability parameters for product...
Example     12 Subjects                                         Randomly                                        Assigned t...
= .                              = .79                                                    Is it                       = 0....
Data Presentation     Anas Bahnassi PhD 2011   20
Anas Bahnassi PhD 2011                                             21Data Presentation
How Equivalence Types are                       No   Same Drug                                   Not                      ...
FDA Codes ofBioequivalence                      Anas Bahnassi PhD 2011                 23
1If a drug product passes official USP or                          Fallacies    BNF standards then this assures       bioa...
In vitro rate of dissolution tests                                                      Fallacies                         ...
PharmacokineticsAnas Bahnassi PhD RPh                           abahnassi@gmail.com                      http://twitter.co...
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Pharmacokinetics: Lecture Five

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Bioavailability and Bioequivalence

Pharmacokinetics: Lecture Five

  1. 1. Bioavailability and Bioequivalence Anas Bahnassi PhD RPh
  2. 2. Lecture ObjectivesUpon the completion of this lecture the student should be able to:• Define terms bioavailability, absolute bioavailability, comparative bioavailability, bioequivalence, therapeutic equivalence, pharmaceutically equivalent products and pharmaceutical alternatives Anas Bahnassi PhD 2011• Explain the difference between bioequivalence and therapeutic equivalence and describe whether bioequivalence will, in all cases, lead to therapeutic equivalence• Calculate absolute and relative bioavailability• Explain the manner in which parameters reflecting rate and extent of absorption are used to determine bioequivalence between two formulations; use equations to calculate these parameters• Explain the first-pass effect and its influence on bioavailability of a drug• Perform calculations to assess bioequivalency by the method employed by the US Food and Drug Administration (FDA)• Explain the FDA rating system for bioequivalency. 2
  3. 3. Bioavailability Definitions The relative amount of an The rate and extent to which the activeadministered dose that reaches the ingredient or therapeutic moiety is general circulation and the rate at absorbed from a product and becomes which this occurs available at the site of drug action Anas Bahnassi PhD 2011 3
  4. 4. Pharmaceutical Therapeutic or Chemical Equivalence Equivalence Means that two or more Two or drug products contain more chemically or equal amounts of the pharmaceutically same therapeutically equivalent active ingredients in identical dosage forms, products essentially and that these dosage produce the same efficacy forms meet the and/or toxicity in the same requirements such as individuals whenpurity, content uniformity administered in anand disintegration time as identicalestablished by the United dosage States Pharmacopeia regimen. and/or National Formulary. Anas Bahnassi PhD 2011 4
  5. 5. Bioequivalence Compare Bioequivalence and Two or more chemically or Therapeutic pharmaceutically equivalent products Equivalence produce comparable bioavailability characteristics in any individual whenadministered in equivalent dosage regimen (parameters compared include the areaunder the plasma concentration versus timecurve (AUC) from time zero to infinity AUC , maximum plasma concentration and the time of peak concentration). Anas Bahnassi PhD 2011 5
  6. 6. Bioavailability Absolute Relative Comparing bioavailability parameters derived from plasma or urine data between two different dosage forms or Comparing AUC or total Xu of two different extravascular routes of extravascular administration to administration intravascular administration Anas Bahnassi PhD 2011 6
  7. 7. imAnas Bahnassi PhD 2011 7
  8. 8. Absolute Bioavailability () ( ) F= () F= ( ) () ( ) F= () × F= × ( ) Anas Bahnassi PhD 2011 8
  9. 9. Relative Bioavailability () ( ) F= × F= × () ( ) Anas Bahnassi PhD 2011 9
  10. 10. () F= × () A type of relative bioavailabilityBioequivalence We compare an innovative product (standard) with generic product Anas Bahnassi PhD 2011 10
  11. 11. Excipients Particle size Formulation Factors Crystalline or amorphous Hydrous or anhydrousFactors affecting Bioavailability Gastric emptying Intestinal motility Physiological Factors GIT pH changes Changes in Anas Bahnassi PhD 2011 intestinal wall 11
  12. 12. The First Pass Effect The fraction, f, of orally administered drug thatsuccessfully passes through gut lumen and gut wall is then taken via the hepatic portal vein to the liver, where metabolism of the drug by enzymes may take place.This extraction by the liver of orally administered drug is called the first pass effect. Anas Bahnassi PhD 2011 12
  13. 13. Determination of the area under the plasma concentration–time curve from intravenous bolus administration ∞ 0 − = = . 0 ∞ ∞ 0 − 0 − = . = . = − ∞ − −0 0 0 Extra- ∞ vascular 0 0 = . = = = 0 Anas Bahnassi PhD 2011 13
  14. 14. Determination of the area under the plasma concentration–time curve from extravascular administration ∞ 0 = − − − = . ( − ) 0 ∞ 0 = . = − − − . ( − ) 0 0 = − − − ∞ ( − ) 0 − 0 ( )0 = = = ( − ) Anas Bahnassi PhD 2011 14
  15. 15. CmaxAssessing Rate ofAbsorption means comparing: tmax Peak Peak Time (tmax) Concentration (Cmax) Anas Bahnassi PhD 2011 15
  16. 16. Bioavailability TestingAdminister Drug to Minimum 12 For RelativeHealthy Individuals, Subjects Bioavailability ApplyAnalyze Plasma and Crossover Design Normally 18-24 Urine SamplesInformed Conscent Fast Volunteers Medical Check up OvernightLaboratory Testing Anas Bahnassi PhD 2011 16
  17. 17. Bioavailability Testing1. Check the criteria for bioavailability testing.2. Compare bioavailability parameters for products3. being tested: AUC, peak plasma concentration, peak time and/or amount of drug excreted in urine (Xu).4. Examine the information provided for statistical analysis.5. Determine the percentage differences for each parameter between products being tested.6. Apply the 20% rule as a rough indicator in the absence of statistical analysis.7. Know the use of the drug being tested: is onset of action more important or duration? What is the therapeutic range? Is it narrow or broad? Anas Bahnassi PhD 2011 17
  18. 18. Example 12 Subjects Randomly Assigned to 2 groups (6/6) 250mg of 250mg of BrandGeneric Drug Drug Anas Bahnassi PhD 2011 18
  19. 19. = . = .79 Is it = 0.9083 Anas Bahnassi PhD 2011 acceptable? 19
  20. 20. Data Presentation Anas Bahnassi PhD 2011 20
  21. 21. Anas Bahnassi PhD 2011 21Data Presentation
  22. 22. How Equivalence Types are No Same Drug Not Determined Yes Equivalent Therapeutic Same Amount of EquivalentActive Ingredient in No Pharmaceutical identical dosage Alternative form Should Result in Yes Yes Significant Yes Bioequivalent Pharmaceutical difference in Equivalent rate or extent of Absorption Anas Bahnassi PhD 2011 Bioinequivalent 22
  23. 23. FDA Codes ofBioequivalence Anas Bahnassi PhD 2011 23
  24. 24. 1If a drug product passes official USP or Fallacies BNF standards then this assures bioavailability in humans. 2 Bioavailability must always be related to pharmacological effects or clinical response. If drug products containing the same active ingredient(s) do have 3 different bioavailabilities and/or different therapeutic differences, then this will be recognized in clinical use of the drug and reported in the scientific literature. Anas Bahnassi PhD 2011 24
  25. 25. In vitro rate of dissolution tests Fallacies 4 can disclose differences in bioavailability and/or therapeutic effects without parallel data on the same drug products in human. Differences in bioavailability From one manufacturer’s product to the next are less important 5 than differences between the Anas Bahnassi PhD 2011 labeled dose and average potency as determined by chemical assay in vitro or in vivo in an animal system. 25
  26. 26. PharmacokineticsAnas Bahnassi PhD RPh abahnassi@gmail.com http://twitter.com/abahnassi http://www.linkedin.com/in/abahnassi http://www.udemy.com/pharmacokinetics http://www.slideshare.net/abahnassi attribution – non-commercial – share alike
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