Bioequivalence

1
BioequivalenceIn Vitro-In Vivo Correlations
Study Design Data Interpretationbased on
theBiopharmaceutic Classification System

• Robert G. Buice, Ph.D.

2
Introduction

• From Oral Drug Product Administration to Drug
  Activity
• Dissolution
• Absorption
• Distribution
• Clearance (Metabolic / Renal)
• PK Profile in Plasma, Fluids, Tissues
• Clinical Efficacy Adverse Events

3
Introduction

• From Oral Drug Product Administration to Drug
  Activity
• Dissolution
• Absorption
• Distribution
• Clearance (Metabolic / Renal)
• PK Profile in Plasma, Fluids, Tissues
• Clinical Efficacy Adverse Events

4
Introduction

• 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

5
Introduction

• 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)

6
Introduction

• 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

7
Introduction

• 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 ???

8
Introduction

• 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

9
Introduction

• 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

10
Introduction

• 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 ???

11
Introduction

• 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 Variability
• Similar concentration - time profiles at all GI
  membrane surfaces accordingly
• Similar overall rate extent of absorption
• BioINequivalence Unless study properly powered

12
Introduction

• BE Sources of Variability in PK
• Low GI Permeability
• 1st Pass Metabolism
• Neither relates to the formulation

13
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

14
Introduction

• 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

15
Introduction
16
Introduction
17
Objectives

• Concepts of BE Study Design
• Probability of Bioequivalence
• Probability of IVIVC
• As related to the BCS

18
Mechanistic Variables

• Mechanistic varaiables that complicate the
  establishment of BE or IVIVC
• Factors that result in bioavailability lt 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 ?

19
Mechanistic Variables

• Mechanistic Variables
• Incomplete release of drug at site
• Insufficient drug in solution at site
• First pass metabolism
• Low g.i. permeability

Addressed by Biopharmaceutics Classification
System
20
Mechanistic Variables

• Mechanistic Variables
• Incomplete release of drug at site
  (formulation)
• Insufficient drug in solution at site
• First pass metabolism
• Low g.i. permeability

Addressed by Biopharmaceutics Classification
System
21
Mechanistic Variables

• Mechanistic Variables
• Incomplete release of drug at site
  (formulation)
• Insufficient drug in solution at site
  (substance)
• First pass metabolism
• Low g.i. permeability

Addressed by Biopharmaceutics Classification
System
22
Mechanistic Variables

• 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)

Addressed by Biopharmaceutics Classification
System
23
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

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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)

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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

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Biopharmaceutics Classification System

• BCS defines 3 numbers (no units)
• An absorption number
• Do dose number
• Dn dissolution number

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Biopharmaceutics Classification System
Absorption Number A function of GI Permeability
to Drug Substance
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Biopharmaceutics Classification System
Effective permeability
Residence time in GI
Radius of GI
Time required for complete absorption
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Biopharmaceutics Classification System

• An lt 1.15
• F lt 0.90
• Permeability Not High

BA in the absence of formulation factors
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Biopharmaceutics Classification System

• An ? 1.15
• F ? 0.90
• Permeability High

BA in the absence of formulation factors
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Biopharmaceutics Classification System
Dose Number A function of solubility
of drug substance
Highest Dose Unit
250 mL
Solubility
Solubility Issues
D / Vwater gtgt CS High Do D / Vwater ltlt CS
Low Do
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Biopharmaceutics Classification System
Dissolution Number A function of drug release
from formulation
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Biopharmaceutics Classification System
Diffusivity 5x10-6 cm2/s
Solubility mg/mL
Residence time in GI 180 min
Particle Radius 25 mm
Time required for complete dissolution
Density 1.2 mg/cm3
34
Biopharmaceutics Classification System

• Oral Solution F f(perm) ? An
• First pass metabolism (variability)
• Low g.i. permeability (variability)
• Oral Solid Dosage Form
• F can be less than predicted by An
• Solubility of Substance
• High Do (? 1) Low solubility of highest dose
  unit relative to initial gastric volume
• Release from Formulation Dissolution
• Low Dn (lt 1) Slow release into solution

Absence of formulation
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Biopharmaceutics Classification System
Solubility of Drug Substance

• Highly Soluble Drug Substance
• Low Do (lt 1.0) High solubility (Highest dose
  unit dissolves in initial gastric volume 250mL)
  between pH 1.0 7.5

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Biopharmaceutics Classification System
Solubility of Drug Substance

• Low Solubility Drug Substance
• High Do (? 1.0) Low solubility (Highest dose
  unit will not dissolve in initial gastric volume
  250mL) between pH 1.0 7.5

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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)
• High Dn Rapid release into solution

38
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)
• Low Dn Slower release into solution

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Biopharmaceutics Classification System

• Poorly Soluble Drugs / Slowly Releasing Products
• A B
• A B
• Dn 0.69
  0.36
• Dose (mg) 400 2.5
• Vwater (L) 0.250
  0.250
• CS (mg/L) 32
  17

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Biopharmaceutics Classification System

• Poorly Soluble Drugs / Slowly Releasing Products
• A B
• In 250mL water Initial gastric volume
  
• A B
• Dn 0.69
  0.36
• Dose (mg) 400 2.5
• Vwater (L) 0.250
  0.250
• CS (mg/L) 32
  17
• Do 50 0.59

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Biopharmaceutics Classification System

• Poorly Soluble Drugs / Slowly Releasing Products
• A B
• In 250mL water Initial gastric volume
  
• A B
• Dn 0.69
  0.36
• Dose (mg) 400 2.5
• Vwater (L) 0.250
  0.250
• CS (mg/L) 32
  17
• Do 50 0.59
• Max dissolved (mg) 8.0 mg (D 400mg)
  4.25 mg (D 2.5mg)

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Biopharmaceutics Classification System

• Poorly Soluble Drugs / Slowly Releasing Products
• A B
• Mechanism
• A B
• Dn 0.69
  0.36
• Dose (mg) 400 2.5
• Vwater (L) 0.250
  0.250
• CS (mg/L) 32
  17

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Biopharmaceutics Classification System

• Poorly Soluble Drugs / Slowly Releasing Products
• A B
• Mechanism Equilibrium
  Kinetic
• (Solubility-Limited)
  (Dissolution Rate-Limited)
• A B
• Dn 0.69
  0.36
• Dose (mg) 400 2.5
• Vwater (L) 0.250
  0.250
• CS (mg/L) 32
  17

Equilibrium or Kinetic limitation can result in a
low Dn
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Biopharmaceutics Classification System

• Poorly Soluble Drugs / Slowly Releasing Products
• A B
• A B
• Dn 0.69
  0.36
• Dose (mg) 400 2.5
• Vwater (L) 0.250
  0.250
• CS (mg/L) 32
  17
• Papp gt 14 lt 6

Class II
Class IV
45
Biopharmaceutics Classification System
Applications BE IVIVC

• Do Dn An
• Class I Low High
  High
• Class II Low Low High
• Class II High Low High
• Class III Low High Low
• Class IV Low Low Low
• Class IV High Low Low
• Highly-soluble substance
  Rapidly-releasing formulation
• In vitro / in vivo correlation (IVIVC) highly
  probable

46
Biopharmaceutics Classification System
Applications BE IVIVC

• Do Dn An
• Class I Low High
  High
• Class III Low High Low
• C
• Highly-soluble substance
  Rapidly-releasing formulation
• In vitro / in vivo correlation (IVIVC) highly
  probable

Class I No 1st Pass Bioequivalent
Class III Class I 1st Pass Bioequivalent
if Powered Properly
47
Biopharmaceutics Classification System
Applications BE IVIVC

• Do Dn An
• C
• Class II Low Low High
• Class II High Low High
• C
• Class IV Low Low Low
• Class IV High Low Low
• Highly-soluble substance
  Rapidly-releasing formulation
• In vitro / in vivo correlation (IVIVC) highly
  probable

Low Dn (slow release) can result from Equilibrium
(solubility), Kinetic (dissolution rate),or
Formulation Limitations
Class II Bioequivalent if dissolution data
match at pH 1, pH 4.5, Ph 6.8 (If 1st pass
Power Properly) Highest probably of IVIVC
Especially of Do is low
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Biopharmaceutics Classification System
Applications BE IVIVC

• Do Dn An
• Class II Low Low High
• Class II High Low High
• Class IV Low Low Low
• Class IV High Low Low
• Slow release (low Dn) due to
• Slow Releasing Formulation Might be a Freely
  Soluble Substance (Low Do)
• Any Formulation Kinetic (Dissolution Rated
  Limited) Substance
• Any Formulation Equilibrium (Solubility
  Limited) Substance (High Do)

49
Biopharmaceutics Classification System

• Class I - No significant first pass
• BA High tmax Short
• BE Product is rarely a concern
• Rapidly Dissolving (Single point dissolution
  test)
• Dissolve immediately in the stomach
• Do not precipitate in the duodenum
• BE Study is rarely a concern
• High permeability (Low Variability)
• No resistance at the GI membrane
• BCS Guidance (Sep 00) BE Waiver

50
Biopharmaceutics Classification System

• Class I - Significant 1st Pass
• BA Lower tmax Short
• BE Product is rarely a concern
• Rapidly Dissolving (Single point dissolution
  test)
• Dissolve immediately in the stomach
• Do not precipitate in the duodenum
• BE Study can be a concern
• Permeability high but 1st pass effect ?
  Variability
• Variability (CVanova) can range from moderate to
  high
• BCS Guidance (Sep 00) BE Waiver

51
Biopharmaceutics Classification System

• Class II - No significant 1st Pass
• BA tmax f (dissolution)
• BE Product can be a concern (Do ?)
• Slowly Dissolving (Dissolution profile)
• Match dissolution profiles at pH 1, pH 4.5, pH
  6.8
• If Do Low Dissolution predicts PK (BE) IVIVC
  probable
• Variability can be due to product (RSD)
• BE Study is rarely a concern
• High permeability (Low Variability)

52
Biopharmaceutics Classification System

• Class II - Significant 1st Pass
• BA tmax f (dissolution) but BA will be Lower
• BE Product can be a concern (Do ?)
• Slowly Dissolving (Dissolution profile)
• Match dissolution profiles at lower pH
• If Do Low Dissolution predicts PK (BE) IVIVC
  (variability)
• Variability can be due to product (RSD)
• BE Study can be a concern
• Permeability high but 1st pass effect ?
  Variability
• Variability (CVanova) can range from moderate to
  high

53
Biopharmaceutics Classification System

• Class III - No significant 1st Pass
• BA tmax Less predictable
• Product is rarely a concern
• Rapidly Dissolving (Single point dissolution
  test)
• Dissolves immediately in the stomach
• Does not precipitate in the duodenum
• BE Study can be a concern
• Low Permeability ? Variability
• Variability increases as g.i. permeability
  decreases
• CVanova can range from moderate to high

54
Biopharmaceutics Classification System

• Class III - Significant 1st Pass
• BA tmax Less predictable
• Product is rarely a concern
• Rapidly Dissolving (Single point dissolution
  test)
• Dissolves immediately in the stomach
• Does not precipitate in the duodenum
• BE Study can be a concern
• Low Permeability ? Variability
• Variability increases as g.i. permeability
  decreases
• CVanova can range from moderate to high
• 1st pass effect can add significantly to
  variability

55
Biopharmaceutics Classification System

• Class IV - No significant 1st Pass
• BA tmax Less predictable
• Product can be a concern
• Slowly Dissolving (Dissolution profile)
• Match dissolution profiles at Lower pH (if
  soluble)
• Variability can be due to product (RSD)
• BE Study can be a concern
• Low Permeability ? Variability
• Variability increases as g.i. permeability
  decreases
• CVanova can range from moderate to high

56
Biopharmaceutics Classification System

• Class IV - Significant 1st Pass
• BA tmax Less predictable
• Product can be a concern
• Slowly Dissolving (Dissolution profile)
• Match dissolution profiles at Lower pH (if
  soluble)
• Variability can be due to product (RSD)
• BE Study can be a concern
• Low Permeability ? Variability
• Variability increases as g.i. permeability
  decreases
• CVanova can range from moderate to high
• 1st pass effect can add significantly to
  variability

57
Summary - BCS

• Define those factors that might prevent optimal
  BA, BE, or IVIVC of your substance formulation
• Early in the development process
• Determine BCS Class
• Solubility Dose Number Do
• Release Dissolution Number Dn
• Permeability Absorption Number An

58
Summary - BCS
High Permeability
Low Permeability
BE Variability
BE
Dissolution predicts PK BE if Dissolution
59
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

60
Bioequivalence Study Design

• Estimation of Power
• K. Phillips, Power of the two one-sided tests
  procedure in
• bioequivalence, J. Pharmacokin. Biopharm., 18,
  137 - 144 (1990)
• Describes power value required for projection of
  N and interpretation of data
• Power (Phillips)
• Power Probability of concluding bioequivalence
  if treatments truly are BE
• 1 - Power Probability of concluding
  bioINequivalence if treatments truly are BE
• P

61
Bioequivalence Study Design

• Estimation of Power
• K. Phillips, Power of the two one-sided tests
  procedure in
• bioequivalence, J. Pharmacokin. Biopharm., 18,
  137 - 144 (1990)
• Describes power value required for projection of
  N and interpretation of data
• Power (Phillips)
• Power Probability of concluding bioequivalence
  if treatments truly are BE
• 1 - Power Probability of concluding
  bioINequivalence if treatments truly are BE
• Power 0.20 / 1-Power 0.80 80 Probability
  of concluding bioINequivalence if treatments
  truly are BE

62
Design / Interpretation90 CI vs Power (N)
BE is established by 90 CI around LSM ratios
(T/R) derived from (log transformed) metrics of
peak and total exposure that fall within the
range of 0.80 to 1.25
63
Design / Interpretation90 CI vs Power (N)
??????? T/R 0.91
64
Design / Interpretation90 CI vs Power (N)
???????? T/R 0.91
65
Design / Interpretation90 CI vs Power (N)
??????? T/R 0.91
66
Design / Interpretation90 CI vs Power (N)
??????? T/R 0.95
67
Design / Interpretation90 CI vs Power (N)
???????? T/R 0.95
68
Design / Interpretation90 CI vs Power (N)
??????? T/R 0.95
69
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)

70
When could the system break down ?

• s2 of disposition gt s2 of input
• Class II - Insoluble under specified
• dissolution conditions
• pH 1.0, 4.5, 6.8
• Class III - If excipient alters g.i.
  permeability
• Class I with 1st pass - If excipient alters
  1st pass metabolism

• Each above Class represents at most an extremely
• small portion of drug products

71
Designing a Successful BE Studyusing
theBiopharmaceutic Classification System

• Hypothesis Based upon Experience
• Class I drug products are bioequivalent
• First Pass Metabolism Variability Design
  Issues
• 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
  (???)

72
Designing a Successful BE Studyusing
theBiopharmaceutic 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
  (???)
• Class II drugs that employ surfactant ?

73
Designing a Successful BE Studyusing
theBiopharmaceutic Classification System

• Hypothesis Based upon Experience
• 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