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ชุดนี้บรรยายต่อจาก basic bioequivalence เพื่อให้ เข้าใจความสำคัญการนำ BCS มาใช้ในการตั้งตำรับ ที่ บ.อินเตอร์ไทย 2008
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Bioequivalence In Vitro-In VivoCorrelations
Study Design & Data Interpretationbased 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
Cmax ,Tmax , AUC
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Introduction
Bioavailability CFR ~ Assessed as “Rate” & “Extent” of Absorption Reality ~ Peak (Cmax) & Total (AUC) Exposure
Bioequivalence CFR ~ Equivalent “Rate” & “Extent” of Absorption Reality ~ Equivalent Peak (Cmax) & 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 SystemDrug Products
Solubility PermeabilityClass I High* HighClass II** Low HighClass III High* LowClass 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, 6.885% 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 predictableLess 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 tmax
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 BioINequivalence ~ 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 ~ 1st 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 (Cmax) &
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 Cmax
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 theBiopharmaceutic 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
