Bioequivalence  In Vitro-In VivoCorrelations     Study Design & Data Interpretation based on the Biopharmaceutic Classific...
Introduction <ul><li>Oral Drug Product Administration  </li></ul><ul><li>Drug Activity </li></ul><ul><ul><li>Dissolution <...
C max  ,T max   , AUC
Introduction <ul><li>Bio availability </li></ul><ul><ul><li>CFR ~ Assessed as “Rate” & “Extent” of Absorption </li></ul></...
Concept of BE study <ul><ul><li>Probability of Bioequivalence </li></ul></ul><ul><ul><li>Probability of IVIVC </li></ul></...
Mechanistic Variables <ul><li>Mechanistic variables that complicate the establishment of  BE or IVIVC </li></ul><ul><ul><l...
Mechanistic Variables <ul><ul><ul><li>Incomplete  release  of drug at  site  (formulation) </li></ul></ul></ul><ul><ul><ul...
Biopharmaceutics Classification System Drug Products <ul><li>Solubility Permeability </li></ul><ul><ul><ul><li>Class I  Hi...
 
 
Biopharmaceutics Classification System <ul><li>Highly Soluble Drug Substance </li></ul><ul><ul><li>Highest dose unit is so...
Biopharmaceutics Classification System <ul><li>Highly Permeable Drug (Substance) </li></ul><ul><ul><li>Absolute Bioavailab...
Biopharmaceutics Classification System <ul><li>Solubility of Drug Substance </li></ul><ul><li>Highly Soluble  Drug Substan...
Biopharmaceutics Classification System <ul><li>Release from Formulation( into solution ) </li></ul><ul><li>Rapidly Dissolv...
Biopharmaceutics Classification System <ul><li>How to evaluate BCS drug? </li></ul><ul><li>Class I – No 1st Pass ~ Bioequi...
Predication  <ul><li>If a pharmaceutical formulation </li></ul><ul><ul><li>Immediately releases 100% of drug  substance  i...
Predication <ul><li>If a pharmaceutical formulation </li></ul><ul><ul><li>Slower release  of drug  substance  into  soluti...
Predication <ul><li>If two  pharmaceutically equivalent  formulations </li></ul><ul><ul><li>Demonstrate similar   in vivo ...
Predication <ul><li>If two  pharmaceutically equivalent  formulations </li></ul><ul><ul><li>Demonstrate similar   in vivo ...
Predication <ul><li>If two  pharmaceutically equivalent  formulations </li></ul><ul><ul><li>Demonstrate similar   in vivo ...
Predication <ul><li>If two  pharmaceutically equivalent  formulations </li></ul><ul><ul><li>Demonstrate similar   in vivo ...
Predication <ul><li>Bioequivalence ~  Failure </li></ul><ul><ul><li>Failed  Product   ~   Truly inequivalent Peak (C max )...
Bioequivalence Study Design <ul><li>Sampling schedule </li></ul><ul><ul><li>Adequate data points around C max </li></ul></...
Potential Impact of Failed BE Testing <ul><li>Phase I </li></ul><ul><ul><li>Food Effects </li></ul></ul><ul><ul><li>Dose P...
Designing a Successful BE Study   using the Biopharmaceutic Classification System   <ul><li>Hypothesis Based upon Experien...
Designing a Successful BE Study   using the Biopharmaceutic Classification System <ul><li>Class III drug products are bioe...
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Bioequivalence in adv.

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ชุดนี้บรรยายต่อจาก basic bioequivalence เพื่อให้ เข้าใจความสำคัญการนำ BCS มาใช้ในการตั้งตำรับ ที่ บ.อินเตอร์ไทย 2008

Published in: Business, Health & Medicine

Bioequivalence in adv.

  1. 1. Bioequivalence In Vitro-In VivoCorrelations Study Design & Data Interpretation based on the Biopharmaceutic Classification System Surang Judistprasert
  2. 2. Introduction <ul><li>Oral Drug Product Administration </li></ul><ul><li>Drug Activity </li></ul><ul><ul><li>Dissolution </li></ul></ul><ul><ul><li>Absorption </li></ul></ul><ul><ul><li>Distribution </li></ul></ul><ul><ul><li>Clearance (Metabolic / Renal) </li></ul></ul><ul><ul><li>PK Profile in Plasma, Fluids, Tissues </li></ul></ul><ul><ul><li>Clinical Efficacy & Adverse Events </li></ul></ul>
  3. 3. C max ,T max , AUC
  4. 4. Introduction <ul><li>Bio availability </li></ul><ul><ul><li>CFR ~ Assessed as “Rate” & “Extent” of Absorption </li></ul></ul><ul><ul><li>Reality ~ Peak (C max ) & Total (AUC) Exposure </li></ul></ul><ul><li>Bio equivalence </li></ul><ul><ul><li>CFR ~ Equivalent “Rate” & “Extent” of Absorption </li></ul></ul><ul><ul><li>Reality ~ Equivalent Peak (C max ) & Total (AUC) Exposure </li></ul></ul>
  5. 5. Concept of BE study <ul><ul><li>Probability of Bioequivalence </li></ul></ul><ul><ul><li>Probability of IVIVC </li></ul></ul><ul><ul><li>As related to the Biopharmaceutics Classification System ( BCS) </li></ul></ul>
  6. 6. Mechanistic Variables <ul><li>Mechanistic variables that complicate the establishment of BE or IVIVC </li></ul><ul><ul><li>Factors that result in bioavailability < 100% & variability </li></ul></ul><ul><ul><li>Some can be controlled during drug product development ? </li></ul></ul><ul><ul><li>Understanding those not so easily controlled can help predict the probability of BE or IVIVC from in vitro data ? </li></ul></ul>
  7. 7. Mechanistic Variables <ul><ul><ul><li>Incomplete release of drug at site (formulation) </li></ul></ul></ul><ul><ul><ul><li>Insufficient drug in solution at site (substance) </li></ul></ul></ul><ul><ul><ul><li>First pass metabolism (variability) </li></ul></ul></ul><ul><ul><ul><li>Low g.i. permeability (variability) </li></ul></ul></ul>
  8. 8. Biopharmaceutics Classification System Drug Products <ul><li>Solubility Permeability </li></ul><ul><ul><ul><li>Class I High * High </li></ul></ul></ul><ul><ul><ul><li>Class II ** Low High </li></ul></ul></ul><ul><ul><ul><li>Class III High * Low </li></ul></ul></ul><ul><li>Class IV Low Low </li></ul><ul><li>* Highly-soluble substance in a rapidly-dissolving formulation </li></ul><ul><li>** If Do Low ~ Highest probability of In vitro / in vivo correlation </li></ul>
  9. 11. Biopharmaceutics Classification System <ul><li>Highly Soluble Drug Substance </li></ul><ul><ul><li>Highest dose unit is soluble in 250mL or less between pH 1.0 & 7.5 </li></ul></ul><ul><li>Rapidly Dissolving Product </li></ul><ul><ul><li>900mL media </li></ul></ul><ul><ul><li>UPS Apparatus I (100rpm) or II (50rpm) </li></ul></ul><ul><ul><ul><li>pH 1, 4.5, 6.8 </li></ul></ul></ul><ul><ul><ul><li>85% in solution in 30min (15min to avoid F2) </li></ul></ul></ul><ul><li>Classification is theoretically based on </li></ul><ul><ul><li>Solubility of Drug substance </li></ul></ul><ul><ul><li>Release from formulation into solution ( Dissolution ) </li></ul></ul>
  10. 12. Biopharmaceutics Classification System <ul><li>Highly Permeable Drug (Substance) </li></ul><ul><ul><li>Absolute Bioavailability ≳ 90% </li></ul></ul><ul><ul><li>Mass Balance Recovery ≳ 90% </li></ul></ul><ul><ul><li>In vitro methods (Caco-2 Cells) </li></ul></ul><ul><li>Permeability (apparent) depends upon: </li></ul><ul><ul><li>Transport across GI wall </li></ul></ul><ul><ul><li>Site of Absorption </li></ul></ul><ul><ul><ul><li>Drug has to be in solution at the absorption site </li></ul></ul></ul><ul><ul><ul><li>Drug has to be in contact with the site for adequate time </li></ul></ul></ul>
  11. 13. Biopharmaceutics Classification System <ul><li>Solubility of Drug Substance </li></ul><ul><li>Highly Soluble Drug Substance </li></ul><ul><ul><li>High solubility (Highest dose unit dissolves in initial gastric volume ~ 250mL) between pH 1.0 & 7.5 </li></ul></ul><ul><li>Low Solubility Drug Substance </li></ul><ul><ul><li>Low solubility (Highest dose unit will not dissolve in initial gastric volume ~ 250mL) between pH 1.0 & 7.5 </li></ul></ul>
  12. 14. Biopharmaceutics Classification System <ul><li>Release from Formulation( into solution ) </li></ul><ul><li>Rapidly Dissolving Product </li></ul><ul><li>900mL media </li></ul><ul><ul><li>UPS Apparatus I (100rpm) or II (50rpm) </li></ul></ul><ul><ul><ul><li>pH 1, 4.5, 6.8 </li></ul></ul></ul><ul><ul><ul><li>85% in solution in 30min (15min to avoid F2) </li></ul></ul></ul>
  13. 15. Biopharmaceutics Classification System <ul><li>How to evaluate BCS drug? </li></ul><ul><li>Class I – No 1st Pass ~ Bioequivalent </li></ul><ul><li>Class III & Class I + 1st Pass ~ Bioequivalent if Powered Properly </li></ul><ul><li>Class II ~ Bioequivalent if dissolution data match at pH 1, pH 4.5, Ph 6.8 (If 1st pass ~ Power Properly) </li></ul><ul><li>Class IV ~ Less predictable </li></ul>
  14. 16. Predication <ul><li>If a pharmaceutical formulation </li></ul><ul><ul><li>Immediately releases 100% of drug substance into solution at the site of absorption & </li></ul></ul><ul><ul><li>If GI membrane transport is not restricted </li></ul></ul><ul><li>We might expect </li></ul><ul><ul><li>Rapid rate & optimal extent of absorption </li></ul></ul><ul><ul><li>High Absolute Bioavialbility </li></ul></ul><ul><ul><li>Short t max </li></ul></ul>
  15. 17. Predication <ul><li>If a pharmaceutical formulation </li></ul><ul><ul><li>Slower release of drug substance into solution at the site of absorption & </li></ul></ul><ul><ul><li>If GI membrane transport is not restricted </li></ul></ul><ul><li>We might expect </li></ul><ul><ul><li>in vivo dissolution to correlate with input (absorption) </li></ul></ul><ul><ul><li>in vitro release to predict PK profile </li></ul></ul><ul><ul><li>in vitro - in vivo correlation (IVIVC) </li></ul></ul>
  16. 18. Predication <ul><li>If two pharmaceutically equivalent formulations </li></ul><ul><ul><li>Demonstrate similar in vivo dissolution under all GI conditions & </li></ul></ul><ul><ul><li>If GI membrane transport is not restricted </li></ul></ul><ul><li>We expect </li></ul><ul><ul><li>Similar concentration - time profiles at all GI membrane surfaces & accordingly </li></ul></ul><ul><ul><li>Similar overall rate & extent of absorption </li></ul></ul><ul><ul><li>Bioequivalence </li></ul></ul>
  17. 19. Predication <ul><li>If two pharmaceutically equivalent formulations </li></ul><ul><ul><li>Demonstrate similar in vivo dissolution under all GI conditions & </li></ul></ul><ul><ul><li>If GI membrane transport is restricted </li></ul></ul><ul><li>We expect </li></ul><ul><ul><li>Similar concentration - time profiles at all GI membrane surfaces & accordingly </li></ul></ul><ul><ul><li>Similar overall rate & extent of absorption </li></ul></ul><ul><ul><li>Bioequivalence ??? </li></ul></ul>
  18. 20. Predication <ul><li>If two pharmaceutically equivalent formulations </li></ul><ul><ul><li>Demonstrate similar in vivo dissolution under all GI conditions & </li></ul></ul><ul><ul><li>If GI membrane transport is restricted </li></ul></ul><ul><li>We expect ~ Variability </li></ul><ul><ul><li>Similar concentration - time profiles at all GI membrane surfaces & accordingly </li></ul></ul><ul><ul><li>Similar overall rate & extent of absorption </li></ul></ul><ul><ul><li>Bio IN equivalence ~ Unless study properly powered </li></ul></ul>
  19. 21. Predication <ul><li>If two pharmaceutically equivalent formulations </li></ul><ul><ul><li>Demonstrate similar in vivo dissolution under all GI conditions & </li></ul></ul><ul><ul><li>If GI membrane transport is not restricted ~ 1 st Pass </li></ul></ul><ul><li>We expect </li></ul><ul><ul><li>Similar concentration - time profiles at all GI membrane surfaces & accordingly </li></ul></ul><ul><ul><li>Similar overall rate & extent of absorption </li></ul></ul><ul><ul><li>Bioequivalence ??? </li></ul></ul>
  20. 22. Predication <ul><li>Bioequivalence ~ Failure </li></ul><ul><ul><li>Failed Product ~ Truly inequivalent Peak (C max ) & Total (AUC) Exposure </li></ul></ul><ul><ul><li>Failed Study ~ Study Design Issues </li></ul></ul><ul><ul><ul><li>Variability ~ Low Power of the ANOVA </li></ul></ul></ul><ul><ul><ul><ul><li>Low GI Permeability </li></ul></ul></ul></ul><ul><ul><ul><ul><li>First Pass Metabolism </li></ul></ul></ul></ul>
  21. 23. Bioequivalence Study Design <ul><li>Sampling schedule </li></ul><ul><ul><li>Adequate data points around C max </li></ul></ul><ul><ul><li>Cover at least 3 half-lives from dose </li></ul></ul><ul><li>Number of subjects </li></ul><ul><ul><li>Power of the ANOVA ≥ 80% </li></ul></ul><ul><ul><li>Power ~ Probability of concluding bioequivalence if treatments truly are BE </li></ul></ul>
  22. 24. Potential Impact of Failed BE Testing <ul><li>Phase I </li></ul><ul><ul><li>Food Effects </li></ul></ul><ul><ul><li>Dose Proportionality </li></ul></ul><ul><ul><li>Dose dumping from CR tablet broken at the score </li></ul></ul><ul><ul><li>Drug-Drug Interactions </li></ul></ul><ul><li>BE Studies </li></ul><ul><ul><ul><li>SUPAC </li></ul></ul></ul><ul><ul><ul><li>Site Transfers </li></ul></ul></ul><ul><ul><ul><li>ANDA (Pilot & Pivotal BE Studies) </li></ul></ul></ul>
  23. 25. Designing a Successful BE Study using the Biopharmaceutic Classification System <ul><li>Hypothesis Based upon Experience </li></ul><ul><li>Class I drug products are bioequivalent </li></ul><ul><ul><ul><li>First Pass Metabolism ~ Variability ~ Design Issues </li></ul></ul></ul><ul><ul><ul><li>Certain excipients might alter g.i. permeability (???) </li></ul></ul></ul><ul><ul><ul><li>Guidance permits BE waiver </li></ul></ul></ul><ul><li>Class II drug products are usually bioequivalent if dissolution profiles match (pH 1, pH 4.5, pH 6.8) </li></ul><ul><ul><li>If first Pass Metabolism ~ Variability ~ Design Issues </li></ul></ul><ul><ul><li>Certain excipients might alter g.i. permeability (???) </li></ul></ul>
  24. 26. Designing a Successful BE Study using the Biopharmaceutic Classification System <ul><li>Class III drug products are bioequivalent if study is powered account for variability </li></ul><ul><ul><li>Lower permeability = higher variability ~Design Issues </li></ul></ul><ul><ul><li>If first Pass Metabolism ~ Variability ~ Design Issues </li></ul></ul><ul><ul><li>Certain excipients alter g.i. permeability </li></ul></ul><ul><li>Class IV drug products are often unpredictable </li></ul>
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