![Fundamental Considerations in the Development of Biorelevant Dissolution Test and Essentials of
IVIVC in Drug Development
Preface
The in vitro dissolution test has emerged as the single most crucial test that has the potential to predict in
vivo availability. While dissolution testing is a regular quality control procedure, it plays a critical
role during all phases of drug (formulation) development. Thus, the dissolution test can be employed
prospectively – while developing a formulation with the appropriate drug release characteristics, and
retrospectively – to assess whether a dosage form is releasing the drug at prescribed/predetermined
rate and extent from batch-to-batch. The principal assumption underlying these two applications of
this test is that the dissolution test is able to adequately represent, if not predict, the biological
performance, i.e., bioavailability, of the drug.
There is a need to understand what it takes to develop a ‘Biorelevant Dissolution Test’ method which can
accomplish the abovementioned attributes. Issues concerning the dissolution process, the dissolution
test methodology, factors that influence dissolution process and thereby the dissolution performance,
criteria for selection of a dissolution test method, ways to compute and interpret dissolution data,
methods to determine and interpret IVIVC, are but a few of the many factors that need to be
comprehensively evaluated during the development of a dissolution test. Consequently, the
dissolution test method development is often challenging to the professionals working in drug
product development.
As of date, in vitro dissolution tests seem to be the most reliable predictors of in vivo availability. Although
official tests have great practical value, the fact that there is still a need for a test more directly
related to bioavailability has been recognized. While the bioavailability of drug substances and drug
products in humans can provide a confirmatory evidence of a potential relationship between
dissolution and physiological availability, it is often impractical to perform extensive and expensive
human testing. As a result, the essentials of what is involved in developing and demonstrating an in
vitro - in vivo correlation is necessary.
The presentation will focus on fundamental considerations in the development of 'Biorelevant Dissolution
Test' and understanding the essentials of IVIVC in drug product development.
The author (UVB) wishes to acknowledge with gratitude Millennium Pharmaceuticals Inc., Cambridge,
MA 02139 for sponsoring this program. UVB is indebted to his wife Suneeta for her continuous
unselfish support. Last, but not the least, UVB would like to thank all the well wishers for their
support that is often taken for granted, however, needs to be recognized.
Umesh V. Banakar, Ph.D., Professor and President, Banakar Consulting Services, Carmel, IN 46032
[umeshbanakar@juno.com]](https://image.slidesharecdn.com/novartis1dpresn082812-130604060113-phpapp01/85/test-2-320.jpg)
![Dissolution Method
Development
– Intrinsic dissolution
• Determination of intrinsic
dissolution rate constant
• Low and high K intrinsic
• Implications and projections
– Physical and chemical
parameters
• Drug substance / active
ingredient
• Drug substance + excipient
combination
• [D + excipient] and process
• Dosage form / drug carrier
system
– Solubility
– Crystal structure
– Other](https://image.slidesharecdn.com/novartis1dpresn082812-130604060113-phpapp01/85/test-28-320.jpg)
![Case Study 3
• FDC
• Low dose + high dose
• Poor + high solubility
• OD
• Significantly different Tmaxs [2]
• Significantly different half-lifes
[2]
• No metabolite](https://image.slidesharecdn.com/novartis1dpresn082812-130604060113-phpapp01/85/test-54-320.jpg)
![Such surrogate tests could impact
various stages of drug development
including setting of quality
specifications of the final
product, provided an appropriate
in vivo – in vitro correlation
[IVIVC] can be established.
The place and significance of such
IVIVCs is most encountered during
the assessment of a drug product
under development to potentially
predict its bioefficacy and possibly
its ultimate therapeutic efficacy,
among others.
UVB](https://image.slidesharecdn.com/novartis1dpresn082812-130604060113-phpapp01/85/test-63-320.jpg)
![In vivo vs in vitro system
inherent differences ….2
Duration of test ….
In vitro dissolution test:
IR products – 0.5 h – 2 h
MR products – 3 h – 30 h
Bioavailability test: 5 x elimn. Half-life
(t1/2)
___________________
Fluoxetene 20 mg Capsules (Prozaic)
Dissolution Test Duration: 120 min [2 h]
Bioavailability Duration: 5 x 80 h = 400 h
UVB](https://image.slidesharecdn.com/novartis1dpresn082812-130604060113-phpapp01/85/test-77-320.jpg)
![In vivo vs in vitro system
inherent differences ….3
Functionality of test (1st order vs
arithmatic)
Dissolution/Drug Release function: Arithmetic Y
as f(X)
Bioavailability function: First Order – ln(Y) as f(X)
[Exponential]
Factors influencing bioavailoability have long time to
express ….
Discriminatory - Bio-relevant dissolution test is
required –
drug-specific
product-specific
UVB](https://image.slidesharecdn.com/novartis1dpresn082812-130604060113-phpapp01/85/test-78-320.jpg)
![In vivo vs in vitro system
inherent differences ….8
Mathematical vs clinical …………
[Semi]quantitative based correlations
between bioavailability (parameters)
and dissolution (parameters) are
explored ….
Pharmacokinetic (bioavailability) –
Pharmacodynamic (clinical) correlation
is presumed ….
UVB](https://image.slidesharecdn.com/novartis1dpresn082812-130604060113-phpapp01/85/test-83-320.jpg)
![Basics of In Vitro – In Vivo Correlations IVIVC
….12
• Developing a Correlation
– Behavior such that drug release is
independent of variables studied
• General, robust Level A correlation
– Behavior such that drug release is
dependent on variables of dissolution
• Establish conditions that best correlate
with in vivo [discriminatory]
UVB](https://image.slidesharecdn.com/novartis1dpresn082812-130604060113-phpapp01/85/test-98-320.jpg)
![Bioavailability Assessment
• PK Parameters (BA Investigations)
– Absolute Bioavailability [F]
• F = [(AUC po) * Dose po] / [(AUC
i.v) * Dose i.v]
– Relative Bioavailability [f]
• F or F rel = [(AUC test) * Dose test]
/ [(AUC ref) * Dose ref]
– Half-Life = 0.693 / terminal phase rate
constant
= 0.693 / β
– AUC (Cp as a function of time)
• AUC t1 – t2 = 0.5 * (c1 + c2) * (t2 –
t1)……..
– AUC 0 → * = AUC 0 → t last + AUC t last → inf
= AUC 0 → t + tail-end
correction
= AUC 0 → t + Cp last / β](https://image.slidesharecdn.com/novartis1dpresn082812-130604060113-phpapp01/85/test-110-320.jpg)
More Related Content
test
- 1. Fundamental Considerations inthe Development of Biorelevant Dissolution Test and Essentials of IVIVC in Drug Development 1-Day Intensive Program Umesh V. Banakar, PhD Professor & President Banakar Consulting Services Carmel, IN 46032 USA Presented to Novartis (India) Ltd. Hyderabad, INDIA Sponsored by Sotax (India) Ltd Mumbai, INDIA August 28, 2012
- 2. Fundamental Considerations inthe Development of Biorelevant Dissolution Test and Essentials of IVIVC in Drug Development Preface The in vitro dissolution test has emerged as the single most crucial test that has the potential to predict in vivo availability. While dissolution testing is a regular quality control procedure, it plays a critical role during all phases of drug (formulation) development. Thus, the dissolution test can be employed prospectively – while developing a formulation with the appropriate drug release characteristics, and retrospectively – to assess whether a dosage form is releasing the drug at prescribed/predetermined rate and extent from batch-to-batch. The principal assumption underlying these two applications of this test is that the dissolution test is able to adequately represent, if not predict, the biological performance, i.e., bioavailability, of the drug. There is a need to understand what it takes to develop a ‘Biorelevant Dissolution Test’ method which can accomplish the abovementioned attributes. Issues concerning the dissolution process, the dissolution test methodology, factors that influence dissolution process and thereby the dissolution performance, criteria for selection of a dissolution test method, ways to compute and interpret dissolution data, methods to determine and interpret IVIVC, are but a few of the many factors that need to be comprehensively evaluated during the development of a dissolution test. Consequently, the dissolution test method development is often challenging to the professionals working in drug product development. As of date, in vitro dissolution tests seem to be the most reliable predictors of in vivo availability. Although official tests have great practical value, the fact that there is still a need for a test more directly related to bioavailability has been recognized. While the bioavailability of drug substances and drug products in humans can provide a confirmatory evidence of a potential relationship between dissolution and physiological availability, it is often impractical to perform extensive and expensive human testing. As a result, the essentials of what is involved in developing and demonstrating an in vitro - in vivo correlation is necessary. The presentation will focus on fundamental considerations in the development of 'Biorelevant Dissolution Test' and understanding the essentials of IVIVC in drug product development. The author (UVB) wishes to acknowledge with gratitude Millennium Pharmaceuticals Inc., Cambridge, MA 02139 for sponsoring this program. UVB is indebted to his wife Suneeta for her continuous unselfish support. Last, but not the least, UVB would like to thank all the well wishers for their support that is often taken for granted, however, needs to be recognized. Umesh V. Banakar, Ph.D., Professor and President, Banakar Consulting Services, Carmel, IN 46032 [[email protected]]
- 3. Fundamental Considerations inthe Development of Biorelevant Dissolution Test and Essentials of IVIVC in Drug Development Umesh Banakar, PhD, Professor and President, Banakar Consulting Services, Carmel, IN 46032 USA Table of Contents I. Introduction, Objectives and Scope II. Biorelevant Dissolution Test Method Development Part 1: BCS Considerations III. Biorelevant Dissolution Test Method Development Part 2: Compendial versus Noncompendial IV. Biorelevant Dissolution Test Method Development Part 3: IR Solid Dosage Forms V. Biorelevant Dissolution Test Method Development Part 4: MR Solid Dosage Forms VI. Biorelevant Dissolution Test Method Development Part 5: Regulatory Considerations VII. In Vitro - In Vivo Correlations Part 1: Basics of Correlation VIII. In Vitro - In Vivo Correlations Part 2: Difficulties in Correlating Dissolution and Bioavailability IX. In Vitro - In Vivo Correlations Part 3: Regulatory Perspective X. In Vitro - In Vivo Correlations Part 4: Data Analyses - in vitro and in vivo XI. In Vitro - In Vivo Correlations Part 5: Setting-up IVIVC XII. In Vitro - In Vivo Correlations Part 6: Applications and Perspectives XIII. Concluding Remarks Q &A
- 4. Module I • Introduction •Objective and Scope Umesh V. Banakar, PhD
- 5. Pharmaceutical Systems (Types) –Physical property based • Disintegration • Non-disintegrating – Functional property based (regulatory based) • Immediate release • Modified release – Enteric coated – Others (PR/SR/CR/DR/ER/…) – Carrier system based • Solid (dissolution testing required) • Semi-solid (dissolution testing required) • Liquids (dissolution testing required except for true solutions BCS-UVB
- 6. A K1 BK2 C IVIVC? A: Drug in dosage form B: Drug dissolved in the gut C: Drug in blood/systemic circulation D: Drug dissolved in in vitro dissolution system K1: in vivo dissolution rate constant K2: in vivo drug absorption rate constant K3: in vitro dissolution rate constant UVB Correlation K3 D
- 7. Objectives and Scope •Fundamentalsof Dissolution Testing •Biorelevant Dissolution •Discriminative Biorelevant Dissolution Testing •Basics of IVIVC •Can dissolution be correlated to bioavailability •Essentials in Setting up IVIVC • Beyond Traditional IVIVC (time permitting) Outside the scope …… •Drug specific method development •USP Dissolution Methods - instrumentation •Mechanics/mathematics of IVIVC •Interpretation and Drug Specific IVIVC UVB
- 8. Module II Biorelevant DissolutionTest Method Development Part 1: BCS Considerations Umesh V. Banakar, PhD
- 9. • Revisiting BCS •Designing Intrinsic Dissolution Test • Interpretation of Results and Drawing Inferences • Connecting Intrinsic and Apparent Dissolution Test UVB
- 10. • Biopharmaceutics Classification System(BCS) – IR • Based on Drug Solubility and Permeability – Case 1: High Solubility – High Permeability – Case 2: Low Solubility – High Permeability – Case 3: High Solubility – Low Permeability – Case 4: Low Solubility – Low Permeability
- 11. • Requirements – Whatis the rate limiting step in vivo? – Can this step be measured in vitro?
- 13. Designing Intrinsic Dissolution Test •AgitationIntensity •pH of dissolution medium •Sink volume •Particle size •Solubility class •Target dosage form •Others
- 14. Intrinsic Dissolution Test Interpretationof results and drawing conclusions: •Agitation Intensity In/Dependency •pH In/Dependency •Sink volume – Dose size •Particle size impact •Solubility class •Target dosage form •Magnitude of Kin •Others UVB
- 15. Intrinsic and Apparent DissolutionTest Relationship •Agitation Intensity In/Dependency •pH In/Dependency •Sink volume – Dose size •Particle size impact •Solubility class •Target dosage form •Magnitude of Kin •Others UVB
- 16. Module III Biorelevant DissolutionTest Method Development Part 2: Compendial versus Noncompendial Umesh V. Banakar, PhD
- 17. • Current USP XXV •Dissolution <711> – Apparatus 1 – Apparatus 2 Dissolution <711> – Apparatus 1 – Apparatus 2 – Apparatus 3 – Apparatus 4 – Apparatus 5 – Apparatus 6 – Apparatus 7 UVB
- 18. Bioavailability Parameters and Dissolution •Absorption • Distribution • Metabolism • Elimination / excretion • Dissolution rate constant (in vitro / in vivo) • Total amount dissolved (in vitro / in vivo) • Which one is dissolution dependent? UVB
- 19. BIORELEVANCE OF DISOLUTION TEST •Solubility of drug • Partitioning of drug (logP) • Type of formulation • Site of drug administration • Potential of drug release/dissolution • Is dissolution rate-limited absorption UVB
- 20. BIORELEVANCE OF DISOLUTION TEST-2 • Potential site of drug absorption • In vivo site where dissolution criteria are met • In vivo where most likely IVIVC is observed • Chemistry of the drug • Physicochemical properties of the drug • Intrinsic dissolution consideration UVB
- 21. PHARMACEUTICAL SYSTEMS AND DISSOLUTIONTEST CONDITIONS • Immediate Release formulations • Modified Release formulations • Disintegrating/Non- disintegrating systems • Solid, Semi-solid and Liquid formulations • Dose strength and Drug:Excipient Ratio UVB
- 22. PHARMACEUTICAL SYSTEMS AND DISSOLUTIONTEST CONDITIONS - 2 • Drug solubility and sink conditions • Influence and importance of hydrodynamics • pH profiling: Necessary or otherwise • Physiological considerations • Active metabolite considerations UVB
- 23. PHARMACEUTICAL SYSTEMS AND DISSOLUTIONTEST CONDITIONS - 3 • In vivo dissolution site considerations • Absorption site considerations • BA under fasted and fed states • Simulation of dissolution under fed state • In vivo BA, f value, for the drug UVB
- 24. COMPENDIAL DISSOLUTION TESTS AND BIORELEVANCE •Disintegration and Dissolution tests • Dissolution test Assembly(ies) • Compendial dissolution media • Use of solubility modifiers (surfactants, etc.) • Compendial dissolution test medium volume UVB
- 25. COMPENDIAL DISSOLUTION TESTS AND BIORELEVANCE- 2 • Hydrodrynamics in compendial methods • pH profiling or otherwise • Acceptance criteria • Q versus Rate parameter Quality Control Tests !!!! UVB
- 26. NONCOMPENDIAL DISSOLUTION TESTS AND BIORELEVANCE •Modifications in Test Assembly(ies) • Combination of compendial methods • Hydrodynamics modifiers • Nontraditional dissolution media • Solubility modifiers (noncompendial !) • Intrinsic dissolution test UVB
- 27. Development of Suitable Dissolution Method –Europe: no monographs on formulations or individual methods necessary – Critical criteria • Properties of dosage form – Geometry: mono or multi-particulate – Technology: conventional or modified • Properties of drug substance – Solubility – Wettability – Stability – Others
- 28. Dissolution Method Development – Intrinsicdissolution • Determination of intrinsic dissolution rate constant • Low and high K intrinsic • Implications and projections – Physical and chemical parameters • Drug substance / active ingredient • Drug substance + excipient combination • [D + excipient] and process • Dosage form / drug carrier system – Solubility – Crystal structure – Other
- 29. Development of aBiorelevant Dissolution Test (General Scheme) – Determine BCS of the drug and the dosage form – Choice of appropriate test apparatus – Choice of appropriate medium for the test – Dissolution test medium and its characteristics (dissolved gases, nontraditional pHs, enzymes, etc.) – Hydrodynamics (available and optimized) of medium – Duration of the dissolution test with regard to formulation type and drug properties – Setting criteria for evaluation of the test results
- 30. Development of aBiorelevant Dissolution Test (Secondary Considerations) – Relation between intrinsic and apparent dissolution tests – Stage of drug development – Prospective, or retrospective, test development – Test for NDA and / or ANDA product – Test for IR or MR product – Monograph available or otherwise (generics)
- 31. Development of aBiorelevant Dissolution Test – Choice of appropriate test apparatus • Compendial versus noncompendial • Compendial with modification(s) • Can the essential considerations be accommodated? • Drug substance and dosage form requirements
- 32. Development of aBiorelevant Dissolution Test – Choice of appropriate medium for the test – Dissolution test medium and its characteristics (dissolved gases, nontraditional pHs, enzymes, etc.)
- 33. Development of aBiorelevant Dissolution Test – Different media suggested / available • Buffers at pHs: 1.2, 4.5, 6.8, 7.5 • Buffers with or without enzymes • Simulated gastric fluid surfactant • Simulated intestinal fluid • Fasted simulated small intestinal fluid • Fed simulated small intestinal fluid • Ensure plus, milk (fat grades) • Co-solvent systems (solubizers) • Organic solvents • Aerated / deaerated media – Deaeration methods, age, etc. • Others
- 34. Development of aBiorelevant Dissolution Test – Important considerations • Stage of drug development • Volume of dissolution medium • Duration of the test • Type of formulation and formulation excipients • Planarity and turbulence resultant to mixing • Is discrimination or sensitivity the evaluation criterion?
- 35. Development of aBiorelevant Dissolution Test – Duration of the dissolution test with regard to formulation type and drug properties • Type of dosage form: IR or MR • Rapidly dissolving or otherwise • BCS and type of dosage form / drug properties • Sampling protocol • Regions of the profile • Duration of the test and stability of the drug / product
- 36. Development of aBiorelevant Dissolution Test – Setting criteria for evaluation of the test results • Comparative tests • Comparative test results • Establishing in vitro equivalence • Stage of drug development • Pre-biostudies or post-biostudies • Method transfer post IVIVC to QC
- 37. Module IV Biorelevant DissolutionTest Method Development Part 3: IR Solid Dosage Forms Umesh V. Banakar, PhD
- 38. • Strategy developmentfor design • In vitro evaluation of formulations • Biorelevant dissolution test(s) and demonstrating discrimination • Selection of Formulation from prototype to pivotal • Beyond F1/F2 analysis • Potential prediction of in vivo availability and Bioequivalence • Definitive BE studies
- 39. Designing an ImmediateRelease Generic Pharmaceutical API matters most (generally) Route of synthesis – Polymorph(s) Formulation composition/component Others
- 40. Critical physicochemical propertiesof API (s) Crystalinity Particle size and distribution Polymorph(s) considerations Solubility profile – pH and organic solvents Analytical considerations Impurity profile Compatibility with excipient(s) Stability profile (including tracking of impurities) UVB
- 41. Immediate Release Pharmaceutical Biopharmaceuticalconsiderations In vitro Dissolution considerations Compendial/monograph requirements Define dissolution test protocol Biorelevant condition(s) Sampling protocol (honoring monograph reqmts.) Rate assessment should be feasible Set discriminatory criteria Define Acceptance Criteria In vitro Equivalence Assessment F1 and F2 Analyses (all testing conditions) Rate comparisons Extent comparisons In-process formulation and dosage form testing UVB
- 42. Case Study 1 •Poorly soluble drug • No metabolism • Low dose • Short Tmax • Long terminal elimination half-life
- 43. Case Study 2 •Poorly soluble • Relatively low dose • Low BA • Not so short Tmax • Long half-life • Active metabolite
- 44. Module V Biorelevant DissolutionTest Method Development Part 4: MR Solid Dosage Forms Umesh V. Banakar, PhD
- 45. • Defining Rate-limitingcomponent • In vitro evaluation of formulations • Biorelevant dissolution test(s) and demonstrating discrimination • Beyond F1/F2 analysis • Potential prediction of in vivo availability UVB
- 46. Designing Dissolution Method: ModifiedRelease Pharmaceuticals API matters less (generally) Formulation composition/component Processing/Technology Others UVB
- 47. Designing Dissolution Method ModifiedRelease Pharmaceutical Critical physicochemical properties of API (s) Crystalinity, Particle size and distribution Polymorph(s) considerations Solubility profile – pH and organic solvents Analytical considerations Impurity profile Compatibility with excipient(s) Stability profile (including tracking of impurities) Selection of excipients (rationale and function) UVB
- 48. Designing Dissolution Method ModifiedRelease Pharmaceutical In vitro Dissolution considerations Compendial/monograph requirements Define dissolution test protocol Biorelevant condition(s) Technology driven Noncompendial modifications !! Sampling protocol (long duration + Clinical endpoint considns.) Rate assessment of paramount importance Set discriminatory criteria Define Acceptance Criteria UVB
- 49. Designing Dissolution Method ModifiedRelease Pharmaceutical (contd.) In vitro In/Equivalence Assessment F1/F2 Analyses (all testing conditions) Rate comparisons Extent comparisons In-process formulation and dosage form testing UVB
- 50. Case Study 1 •Low dose • Poor solubility • OD • Medium Tmax • Short half-life • No metabolite
- 51. Case Study 2 •Low dose • Poor solubility • OD • Medium Tmax • Short half-life • Active metabolite
- 52.
- 53.
- 54. Case Study 3 •FDC • Low dose + high dose • Poor + high solubility • OD • Significantly different Tmaxs [2] • Significantly different half-lifes [2] • No metabolite
- 55.
- 56. Module VI Biorelevant DissolutionTest Method Development Part 5: Regulatory Expectations Umesh V. Banakar, PhD
- 57. Regulatory Assessment of OralSR/CR Products Biorelevant dissolution assessment (justification) In relation to technology used In relation to the manufacturing process In relation to predicting BA and thereby BE In relation to therapeutic endpoint DEMONSTRATING DISCRIMINATION In relation to „future‟ QC specs others
- 58. Regulatory Assessment of OralSR/CR Products In vitro equivalence Rate controlling step(s) Biorelevant or otherwise In relation to Monograph requirements (if applicable) Potential for predicting in vivo performance Beyond f1 and f2 analyses Release rate analyses Simulation, prediction and Goodness of Fit Others
- 59. Regulatory Assessment of OralSR/CR Products Setting dissolution/drug release specifications (QC) IVIVC based Non-IVIVC based Technology (employed) specific FDA Guidance based Clinical endpoint based Others Justification is mandatory through discriminatory analyses
- 60. Module VII In Vitro- In Vivo Correlations Part 1: Basics of Correlation
- 61. • The processof developing a drug from discovery to the market is long, arduous and challenging, to say the least. • Along the way, one often comes across crossroads with respect to arriving at a reasonable balance between risks and benefits going beyond achieving clinical targets. UVB
- 62. There is aconstant quest for increasing efficiency and cost effectiveness in the drug development process. In this pursuit, a question often surfaces relating to exploring avenues where in vitro surrogate experiments can be developed and used to predict in vivo outcomes. UVB
- 63. Such surrogate testscould impact various stages of drug development including setting of quality specifications of the final product, provided an appropriate in vivo – in vitro correlation [IVIVC] can be established. The place and significance of such IVIVCs is most encountered during the assessment of a drug product under development to potentially predict its bioefficacy and possibly its ultimate therapeutic efficacy, among others. UVB
- 64. “………Establishment of a rationalrelationship between a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form……..The relationship between the two properties, biological and physicochemical, is then expressed quantitatively.” US-FDA guideline/USP <1088>
- 65. • Correlation isdefined as an attempt to explore a relationship between two variables. • Variable may be defined as a process comprising of an input (cause) function and the resultant output (effect). UVB
- 66. • Examples: Dissolution (input)Amount Dissolved (effect) * Characterized as amount of drug dissolved as a function of time • Dissolution (in vivo) Amount in blood (output) * Characterized as plasma-drug- concentration as a function of time Aging (cause) Color of hair!! (effect) UVB (Process) (Process) (Process)
- 67. Correlation – In vitro– In vivo • Physicochemical property – Dissolution • Biological property – Pharmacokinetics – Dependent on system UVB
- 68. • Requirements ofa Correlation (1) – Dependent and independent variables have to be correlatable. – There has to be at least one distinct common factor or similarity between two variables. Otherwise, one is correlating apples with oranges! – Similarity in the process component within two variables is explored UVB
- 69. Requirements of aCorrelation (2) IVIVC in Drug Development The significance of an IVIVC in drug development is established from: • Coefficient of correlation: r • Coefficient of determination: r2 • Coefficient of dependability • Probability factor: p value • Relevance of correlation UVB
- 70. • Types ofCorrelations – Linear (positive and negative) – Exponential (positive and negative) – Polynomial (positive and negative) – Probability / Probit – Others • For simplicity, linear correlation is preferred. UVB
- 71. • Parameters ofa Linear Correlation • Slope Δ y / Δ x • Intercept: y value when x = 0 • Interpretation of Correlation Meaning of a slope: Provides insight into the function represented on the X-axis Meaning of intercept: Provides information about the dependent variable when X is functionally non-existent or not required UVB
- 72. Interpretation of a Correlation(Part 2) In addition to the items listed in Part 1 Statistically sound Should provide an insight into the processes that are correlated or represented UVB
- 73. Module VIII In Vitro- In Vivo Correlations Part 2: Difficulties in Correlating Dissolution and Bioavailability
- 74. A K1 BK2 C IVIVC? A: Drug in dosage form B: Drug dissolved in the gut C: Drug in blood/systemic circulation D: Drug dissolved in in vitro dissolution system K1: in vivo dissolution rate constant K2: in vivo drug absorption rate constant K3: in vitro dissolution rate constant UVB Correlation K3 D
- 75. Mechanics of IVIVC: Challenges Invivo vs in vitro system inherent differences 2-step vs 1-step …. Duration of test …. Functionality of test (1st order vs arithmatic) …. Dissolution dependent function – characterization ? What to correlate: function, response, parameter .. The issue of metabolite vs administered drug …. Regulatory vs realistic correlation !! Mathematical vs clinical ………… What is the ultimate objective of IVIVC ?? UVB
- 76. In vivo vsin vitro system inherent differences….1 2-step vs 1-step …. Dissolution in vivo is a prerequisite for Bioavailability, and not the reverse When in vivo dissolution is the rate- limiting, then chances for predicting bioavailability (IVIVC) are enhanced UVB
- 77. In vivo vsin vitro system inherent differences ….2 Duration of test …. In vitro dissolution test: IR products – 0.5 h – 2 h MR products – 3 h – 30 h Bioavailability test: 5 x elimn. Half-life (t1/2) ___________________ Fluoxetene 20 mg Capsules (Prozaic) Dissolution Test Duration: 120 min [2 h] Bioavailability Duration: 5 x 80 h = 400 h UVB
- 78. In vivo vsin vitro system inherent differences ….3 Functionality of test (1st order vs arithmatic) Dissolution/Drug Release function: Arithmetic Y as f(X) Bioavailability function: First Order – ln(Y) as f(X) [Exponential] Factors influencing bioavailoability have long time to express …. Discriminatory - Bio-relevant dissolution test is required – drug-specific product-specific UVB
- 79. In vivo vsin vitro system inherent differences ….4 Dissolution (in vivo) dependent function in bioavailability process and its characterization ? Absorption is dissolution dependent, however, for establishing IVIVC entire bioavailability performance has to be used (including distribution, and elimination) Dissolution test presumes that post dissolution/release of the drug complete and rapid/instantaneous absorption occurs UVB
- 80. In vivo vsin vitro system inherent differences ….5 What to correlate: function, response, parameter .. Complete in vivo performance (bioavailability) and complete in vitro performance (dissolution) has to be correlated UVB
- 81. In vivo vsin vitro system inherent differences ….6 The issue of active metabolite vs administered drug …. Dissolution Test: Administered drug (parent drug) Bioavailability Test: Active metabolite __________________ Naltrexone and 6-beta-naltrexol) – active metabolite Dissolution Test: Naltrexone from tablet Bioavailability Test: Plasma-6-beta-naltrexol- concn. UVB
- 82. In vivo vsin vitro system inherent differences ….7 Regulatory vs realistic correlation !! UVB
- 83. In vivo vsin vitro system inherent differences ….8 Mathematical vs clinical ………… [Semi]quantitative based correlations between bioavailability (parameters) and dissolution (parameters) are explored …. Pharmacokinetic (bioavailability) – Pharmacodynamic (clinical) correlation is presumed …. UVB
- 84. In vivo vsin vitro system inherent differences ….9 What is the ultimate objective of IVIVC ?? To set up IVIVC based dissolution test (in vitro test) quality specifications to ensure batch-to-batch consistency with respect to quality !!!! UVB
- 85. Correlation Can dissolution and bioavailabilitybe correlated ? Misconception/Myth:- Amount of drug dissolved should equate (correlate) with amount of drug bioavailable (absorbed) The pursuit should be:- Are the changes in the bioavailability performances between formulations predictable in/from the respective dissolution performances of these products ? UVB
- 86. Module IX In Vitro- In Vivo Correlations Part 3: Regulatory Perspective
- 87. Basics of InVitro – In Vivo Correlations IVIVC …1 • Classes of In Vitro – In Vivo Correlations – Pharmacological Correlations: based on clinical observations – Semi-quantitative Correlations: based on blood levels or urinary excretion data – Quantitative Correlations: resultant to absorption kinetics – Most of the published correlations fall within the second class; the most valuable are those based on absorption kinetics. UVB
- 88. Basics of InVitro – In Vivo Correlations IVIVC ….2 • Essentially there are two basic types of correlations that are employed while comparing in vivo – in vitro data: – Quantitative Correlations – Rank Order Correlations UVB
- 89. Basics of InVitro – In Vivo Correlations IVIVC ….3 • IVIVC – Poor Correlations – Differences seen in BA data not seen in dissolution data – Order of rates reversed – Significant differences seen in dissolution tests NOT observed in BA data – Dissolution inconsistent with BA data UVB
- 90. Basics of InVitro – In Vivo Correlations IVIVC ….4 • Methods for Correlation – Numerical deconvolution / convolution – Statistical moment analysis – Model-dependent methods • Loo-Reigelman • Wagner-Nelson – Regression type correlation of distinct single parameters UVB
- 91. Basics of InVitro – In Vivo Correlations IVIVC ….5 – Human data supplied for IVIVC – Bioavailability studies should have enough subjects – IVIVCs use the fasted state – Any in vitro method can be used – Preferred apparatus (1, 2, 3 or 4) – CDER should be consulted if other is used UVB
- 92. Basics of InVitro – In Vivo Correlations IVIVC ….6 •Deciphering Levels of Correlation •Level A / I –Analogous parameters –Complete profiles –Degree of superimposability • Time-scaling factor UVB
- 93. Basics of InVitro – In Vivo Correlations IVIVC ….7 •Deciphering Levels of Correlation •Level B / II –Analogous parameters –Complete profiles –Model independent parameters –PK / Kinetic parameters representing entire function UVB
- 94. Basics of InVitro – In Vivo Correlations IVIVC ….8 • Deciphering Levels of Correlation • Level C / III – Analogous parameters – Complete profiles – Relevant PK / kinetic parameters • Level D / IV (!) – Accidental correlations UVB
- 95. Basics of InVitro – In Vivo Correlations IVIVC ….9 • Developing a Correlation: Procedure for developing a Level A correlation “The plasma level or urinary excretion data obtained in the definitive BA study of the MR DDS are treated by a deconvolution procedure. The resulting data may represent the drug input rate of the dosage form. It is also considered to represent in vivo dissolution when the rate controlling step of the DDS is it dissolution rate. Any deconvolution procedure (i.e. Mass balance or mathematical deconvolution) will produce acceptable results.” UVB
- 96. Basics of InVitro – In Vivo Correlations IVIVC ….10 • Developing a Correlation The batch used in the pivotal BA study is subjected to in vitro dissolution evaluation, and the effect of varying the dissolution conditions investigated –Variables to be studied • Apparatus • Mixing intensity • Dissolution media UVB
- 97. Basics of InVitro – In Vivo Correlations IVIVC ….11 • Developing a Correlation – In vitro dissolution curve is then compared to the drug input rate curve (degree of superimposibility) • Position one curve on another • Comparing equation constants • Plot fraction absorbed in vivo versus fraction released in vitro • For Level A, result would be a straight line with a slope (may be) equal to 1 • Intercept probably not 0 due to lag time UVB
- 98. Basics of InVitro – In Vivo Correlations IVIVC ….12 • Developing a Correlation – Behavior such that drug release is independent of variables studied • General, robust Level A correlation – Behavior such that drug release is dependent on variables of dissolution • Establish conditions that best correlate with in vivo [discriminatory] UVB
- 99. Module X In Vitro- In Vivo Correlations Part 4: Data Analyses - In vitro and In vivo
- 100. Pharmaceutical Systems (Types) –Physical property based • Disintegration • Non-disintegrating – Functional property based (regulatory based) • Immediate release • Modified release – Enteric coated – Others (PR/SR/CR/DR/ER/…) – Carrier system based • Solid (dissolution testing required) • Semi-solid (dissolution testing required) • Liquids (dissolution testing required except for true solutions BCS-UVB
- 103. Computation of Dissolution Measurement – Cumulativeamount of drug released as a function of time – Percent dose related as a function of time – Amount remaining to be released as a function of time UVB
- 104. • Dissolution Profile:Desirable Characteristics – Complete – Frequently / Adequately Sampled – Sensitive / Discriminatory – Reproducible – Validated UVB
- 105. • Questions – Shouldwe be interested in USP specifications – What is dissolution profiling? How does it differ from pH profiling? – Should we be interested in particular regions of the dissolution profile? – Is a complete dissolution profile necessary? If yes, when (Development or QC)? UVB
- 108. Sampling During Dissolution Testing –Frequent and adequate – Should capture critical regions of profile – Provide for discrimination and sensitivity analysis – User friendly UVB
- 109. Dissolution Profile (Critical Components) –IR products • Early-phase dissolution (critical) • Later-phase dissolution (less critical) – MR products (technology-based products) • Early-phase dissolution (critical) • Middle-phase dissolution (less critical) • Later-phase dissolution (critical) UVB
- 110. Bioavailability Assessment • PKParameters (BA Investigations) – Absolute Bioavailability [F] • F = [(AUC po) * Dose po] / [(AUC i.v) * Dose i.v] – Relative Bioavailability [f] • F or F rel = [(AUC test) * Dose test] / [(AUC ref) * Dose ref] – Half-Life = 0.693 / terminal phase rate constant = 0.693 / β – AUC (Cp as a function of time) • AUC t1 – t2 = 0.5 * (c1 + c2) * (t2 – t1)…….. – AUC 0 → * = AUC 0 → t last + AUC t last → inf = AUC 0 → t + tail-end correction = AUC 0 → t + Cp last / β
- 111. Bioavailability Assessment • StatisticalAnalysis Assumptions – Subjects are randomly assigned to study sequences – Variances between groups and treatments are comparable – Main effects for standard minimum 3 x 3 crossover study should be additive (no interactions) UVB
- 112. Bioavailability Assessment Single Dose –AUC 0 → t (trapezoidal rule) – AUC 0 → * (trapezoidal rule + tail-end correction) – Cmax – Tmax – Terminal Phase • Rate constant (apparent) • Half-life (apparent) UVB
- 113. Bioavailability Assessment • Single-DoseFasting Three- Way Crossover BA Study – Subjects • Minimum 24, healthy, 18 – 50 years old, within 10 – 15% of IBW (male or non- pregnant females) • Written, informed consent required – Overnight fast for at least 10 hours – Restrictions – Blood Samples – Subject monitoring UVB
- 114. Bioavailability Assessment • Samplingand Sampling Interval: Reasons and Rationale – Adequate characterization of bioavailability • Rate: Cmax and Tmax • Extent: AUC 0-t AUC 0-* – Complete characterization of bioavailability • 3 – 5 half-lives post administration – Characterization of critical biological processes • Absorption: predominantly pre-Cmax • Elimination: terminal phase or the 4th or 5th half-life period – Acquire adequate number of points on bio-profile – Clinically relevant
- 115. Bioavailability Assessment • SamplingInterval – Some Rules of Thumb – Adequate and subject friendly (as much as possible) – Frequent, but not necessary (minimum 4 – 5 samples during each phase is sufficient) – Should be able to capture the Cmax region – Should be able to capture the clean terminal phase – More frequent during absorption phase – Less frequent during distribution and elimination phase UVB
- 116. Module XI In Vitro- In Vivo Correlations Part 5: Setting up IVIV Correlation
- 117. Frequently Employed Techniques forCorrelating IVIV Data – Numerical Deconvolution / Convolution – Statistical Moment Analysis – Model-Dependent Methods By • Loo-Riegelman • Wagner-Nelson – Regression-Type Correlation of distinct in vivo and single in vitro parameters UVB
- 118. Analogous – Functional similarity –Parametric similarity – Process similarity – Complete profiles – Degree of superimposibility UVB
- 119. Analogous Parameter Employed inIVIVC Determinations In Vitro In Vivo AUC AUC Kr, Kd Ka, Kd, Kr Tinf, Tmax Cmax F(t), T(F), MRT Fa(t), T(Fa) MDT MRT UVB
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- 123. Sample Data Set2 • 3 Unique formulations (F1, F2, and F3) Figure 2. Average In-VitroDissolution(APIRecovered) 0.00% 20.00% 40.00% 60.00% 80.00% 100.00% 0 20 40 60 80 100 120 Time (hrs) AverageIn-VitroDissolution,(APIRecovered) Error Bars = +/- %CV Form ul- ation Ave rag e % CV In- Vitro Perfor mance % LC F1 5.34 109 F2 7.88 91 F3 11.8 2* 98 *Exceeds FDA recommendation <10% F1 F3 F2 f2 values between formulations are all < 50, indicative of dissimilar dissolution
- 124. Curve Fitted Equations SampleData Set 2 In-Vitro Dissolution Y = -a*exp(-k*t) + b Where: Y = % Drug Dissolved t = Time a = The span of dissolution ( 100) b = The asymptote of the dissolution curve ( 100) k = The dissolution rate constant Formu lation k R2 F1 0.815 99.8% F2 0.078 100.0 % F3 0.021 99.7%
- 125. In-Vivo Results (PK) SampleData Set 2 • 3 Unique In- Vivo PK Results (F1, F2, and F3) Pharmacokineticsof API in Swine and Human 0 1 2 3 4 5 6 7 8 9 0 0.25 0.5 1 2 4 6 8 12 18 24 36 48 72 120 144 168 336 504 672 Time (hrs) APIConcentrationinBlood(ng/mL) Error Bars = +/- Standard Deviation Relati ve % Diff Cmax % Diff AUC F1 vs F2 47 35 F2 vs F3 50 22 F2 F3 F1 F1 - Human
- 126. Curve Fitted Equations SampleData Set 2 • In-Vivo (PK) C = a + b*exp(- 0.5*(ln(t/c)/d)^2) Where: – C = Concentration of API (ng/ml) – t = Time (hrs) – a, b, c, and d are constants that define the concentration curve Formula tion R2 F1 (Swine) 96.8% F2 99.0% F3 97.2% F1 (Human) 99.7%
- 127. Level A: FractionalResponse Times Sample Data Set 2 Graph of In-Vitro Dissolution and In-Vivo PK FractionalResponse Times (FRT) y = 6.39x- 1.78 R2 = 0.98 y = 0.87x- 2.62 R2 = 0.97 y = 0.40x- 4.43 R2 = 0.95 -5 0 5 10 15 20 25 30 35 0 10 20 30 40 50 60 70 80 90 In-Vitro Dissolution FRT, (hours) In-VivoPK(%AUC)FRT,(hours) F2 F3 F1 Fraction Dissolved (In-Vitro) vs Fraction Absorbed (In-Vivo, PK)
- 128. Module XII In Vitro- In Vivo Correlations Part 6: Applications and Perspectives
- 129. IVIVC: Applications and Perspectives •Setting QC Specifications • Biowaivers • Dose-proportionate formulations • Performance Based IVIVCs UVB
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- 132. Module XIII Concluding Remarks andQ and A Umesh V. Banakar, PhD
- 133. • Is itpossible to simulate in vivo conditions within the in vitro dissolution test in the laboratory …. • It surely is challenging …….. • More important is – The understanding of the physiological/biological, i.e., in vivo conditions is of paramount importance to design an appropriate biorelevant dissolution test …. • The quest for such a dissolution test continues ….
- 134. Thinking is capital Enterpriseis the way Hard work is the solution His Excellency Dr. A.P.J. Abdul Kalam Hon. President of India Nov. 28, 2007
- 135. THANK YOU Dhanyawaad !! muitoobrigado !!!! [email protected]
- 136. Please …. • Onlyeasy/simple questions that I can answer !!!!
- 137. Umesh V. Banakar,PhD ++ 317 440 7784 (mobile) ++ 317 334 0174 [email protected]