• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
Bioequivalence in adv.
 

Bioequivalence in adv.

on

  • 1,745 views

ชุดนี้บรรยายต่อจาก basic bioequivalence เพื่อให้ เข้าใจความสำคัญการนำ BCS ...

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

Statistics

Views

Total Views
1,745
Views on SlideShare
1,745
Embed Views
0

Actions

Likes
2
Downloads
191
Comments
0

0 Embeds 0

No embeds

Accessibility

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

    Bioequivalence in adv. Bioequivalence in adv. Presentation Transcript

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