wegner nelson method.pdf

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Development, EvaluationDevelopment, Evaluationand Applications of In Vivoand Applications of In Vivo

In Vitro CorrelationsIn Vitro Correlations

Patrick J. Marroum Ph.D.Patrick J. Marroum Ph.D.Office of New Drug QualityOffice of New Drug Quality

AssessmentAssessmentFood and Drug AdministrationFood and Drug Administration


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OutlineOutlineDefinitionsDefinitionsGeneral ConsiderationsGeneral ConsiderationsDevelopment of IVIVCDevelopment of IVIVC MethodologyMethodology

Validation of IVIVCValidation of IVIVC Internal vs external predictabilityInternal vs external predictability CriteriaCriteria

Applications of IVIVCApplications of IVIVC WaiversWaivers Dissolution specificationsDissolution specifications

ConclusionConclusion


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Level A CorrelationLevel A Correlation

Is a point to point relationship betweenIs a point to point relationship betweenin vitro dissolution and the in vivoin vitro dissolution and the in vivoinput rateinput rateUsually is linear but non linearUsually is linear but non linearrelationships can exist and arerelationships can exist and areacceptable by the FDAacceptable by the FDA


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Level A correlationLevel A correlation

0

20

40

60

80

100

0 20 40 60 80 100

% Drug Dissolved

% DrugAbsorbed


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Level B CorrelationLevel B CorrelationThe mean in vitro dissolution time isThe mean in vitro dissolution time iscompared to either the mean residence timecompared to either the mean residence timeor the mean in vivo dissolution timeor the mean in vivo dissolution timeIt utilizes the principle of statistical momentIt utilizes the principle of statistical momentanalysisanalysisnot a point to point correlationnot a point to point correlation

Different profilesDifferent profiles can give the samecan give the sameparameters valuesparameters values


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Level B CorrelationLevel B Correlation

0

2

4

6

8

10

0 5 10 15 20

MDT in vitro

MDTIn vivo


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Level C CorrelationsLevel C Correlations

Establish a single point relationshipEstablish a single point relationship between a dissolution parameter, e.g. % between a dissolution parameter, e.g. %dissolved in 4 hours and adissolved in 4 hours and apharmacokinetic parameter such aspharmacokinetic parameter such asAUC and CMAXAUC and CMAX

Useful in formulation selection andUseful in formulation selection anddevelopment but not for regulatorydevelopment but not for regulatorypurposespurposes


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Multiple Level CMultiple Level C

A multiple Level C correlation relatesA multiple Level C correlation relatesone or several pharmacokineticone or several pharmacokineticparameters to the amount dissolved atparameters to the amount dissolved atseveral time points of the dissolutionseveral time points of the dissolutionprofileprofile


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Level C CorrelationsLevel C Correlations

0

100

200

300

400

500

0 20 40 60 80 100

% Dissolved

C M A X

( n g

/ m l )

D6D9


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Multiple Level C CorrelationMultiple Level C Correlation

0

4 0

8 0

1 2 0

0 10 20Time

% D

i s s o

l v e d

IJKLMNOP

Formulation CMAX AUC

I 260 2623

J 192 2547

K 192 2249

L 163 2365

M 125 1980

N 211 2462

O 151 2057

P 118 2034

0

10 0

20 0

30 0

40 0

50 0

0 20 40 60 80 100

% Dissolved

C M A X

( n g

/ m l )

D6D9


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Level D CorrelationsLevel D Correlations

Rank order correlations are qualitativeRank order correlations are qualitativeand are not considered useful forand are not considered useful forregulatory purposesregulatory purposes


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General ConsiderationsGeneral ConsiderationsIn VivoIn Vivo

Human data are requiredHuman data are requiredNumber of subjects should be sufficient toNumber of subjects should be sufficient tocharacterize the bio performance of the drugcharacterize the bio performance of the drugproductproductData sets I have analyzed included from 6 toData sets I have analyzed included from 6 to36 subjects36 subjects


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General ConsiderationsGeneral ConsiderationsIn VivoIn Vivo

No restrictions on study designsNo restrictions on study designs Crossover design preferredCrossover design preferred Parallel designParallel design Cross study comparisonsCross study comparisons

Inclusion of a reference treatment suchInclusion of a reference treatment suchas:as: Oral solutionOral solution IV solutionIV solution Immediate release productImmediate release product


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General ConsiderationsGeneral ConsiderationsIn VitroIn Vitro

Any in vitro dissolution method can be utilizedAny in vitro dissolution method can be utilizedThe system once defined should be the same forThe system once defined should be the same forall formulations testedall formulations testedThe preferred dissolution appartus is USPThe preferred dissolution appartus is USPapparatus I or II used at compendiallyapparatus I or II used at compendiallyrecognized speedsrecognized speedsAn aqueous medium either water or bufferedAn aqueous medium either water or bufferedsolutions not exceeding pH 6.8 is recommendedsolutions not exceeding pH 6.8 is recommended


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General ConsiderationsGeneral ConsiderationsIn VitroIn Vitro

For poorly soluble drugs, addition of aFor poorly soluble drugs, addition of asurfactant may be appropriatesurfactant may be appropriateIn general non aqueous and hydroalcoholicIn general non aqueous and hydroalcoholicsystems are discouragedsystems are discouragedDissolution profiles should be obtained fromDissolution profiles should be obtained fromat least 12 unitsat least 12 unitsThe coefficient of variation (% CV) for meanThe coefficient of variation (% CV) for meandissolution of a single batch should be lessdissolution of a single batch should be lessthan 10 %than 10 %


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Dissolution ProfilesDissolution Profiles

0

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60

80

100

120

0 5 10 15 20 25

Time (hours)

% D i s s o

l v e


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Plasma ProfilesPlasma Profiles

020406080

100120140160180

0 10 20 30

Time (hours)

C p

( n g

/ m l )


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Fraction of Drug AbsorbedFraction of Drug Absorbed

0

20

40

60

80

100

0 5 10 15

Time (hours)

% A b s o r b e


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Plasma ProfilesPlasma Profiles

020406080

100120140160180

0 10 20 300

10

20

30

40

50

60

70

80

90

100

0 5 10 15

Deconvolution

Time (hours) Time (hours)


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DeconvolutionDeconvolution

Deconvolution of plasma profiles toDeconvolution of plasma profiles toobtain the fraction of drug absorbed forobtain the fraction of drug absorbed foreach corresponding formulationeach corresponding formulationDeconvolution techniques such as:Deconvolution techniques such as: Wagner Nelson Method for 1 compartment modelWagner Nelson Method for 1 compartment model

LooLoo--Riegelman Method for 2 compartment modelRiegelman Method for 2 compartment model Numerical Deconvolution methodsNumerical Deconvolution methods

PC Decon ProgramPC Decon Program


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0

20

40

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100

0 5 10 15

Time (hours)

% A

b s o r b e

d

0

20

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60

80

100

120

0 5 10 15 20 25

Time (hours)

% D

i s s o l v e d

0

20

40

60

80

100

0 20 40 60 80 100

% Drug Dissolved

% DrugAbsorbed


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-10

0

10

20

3040

50

60

0 20 40 60 80

%Dissolved

% A

b s

0

50

100

0 50 100

%Dissolved

% A

b s

0102030405060

7080

0 20 40 60 80 100

%Dissolved

% A

b s

-20

0

20

40

60

80

100

0 20 40 60 80 100

%Dissolved

%Abs

Slow FormulationMedium Formulation

Fast Formulation

All Formulations


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0

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60

80

100

120

0 20 40 60 80 100

% Dissolved

% A

b s o r b e d


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Additional ConsiderationsAdditional Considerations

2 or more formulations with different2 or more formulations with differentrelease ratesrelease ratesDissolution independent of dissolutionDissolution independent of dissolutionconditions, IVIVC developed with oneconditions, IVIVC developed with oneformulation is acceptableformulation is acceptable


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Highest or lowest release formulationsHighest or lowest release formulationscan be dropped outcan be dropped out


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The in vitro dissolution methodologyThe in vitro dissolution methodologyshould adequately discriminateshould adequately discriminate between formulations. between formulations.Dissolution conditions should be theDissolution conditions should be thesame for all the formulations tested insame for all the formulations tested inthe bio studythe bio studyThe dissolution conditions should beThe dissolution conditions should befixed before further evaluation of thefixed before further evaluation of thecorrelation is undertakencorrelation is undertaken


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Scaling FactorsScaling Factors

010

2030405060708090

0 5 10 15 20 25

Time(hours)

% D

o s e

Time Shift

Fabs (t)= Fdiss(t+lag)

% Dissolved% Absorbed

0

102030405060708090

0 10 20 30

Time (hours)

% d o s e

%Dissolved%Absorbed


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Scaling FactorsScaling Factors

0

20

40

60

80

100

0 20 40 60 80 100

0

20

40

60

80

100

0 20 40 60 80 100

Scale Factor

% Drug Dissolveda x% Drug Dissolved

Fabs = a x Fdissa=0.5


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EVALUATION OFEVALUATION OF

PREDICTABILITY OFPREDICTABILITY OF

IVIVC IVIVC

EVALUATION OFEVALUATION OF

PREDICTABILITY OFPREDICTABILITY OF

IVIVC IVIVC


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Plasma profilesPlasma profilesPlasma profilesPlasma profiles

020406080

100120140160180

0 5 10 15 20 25 30

Time (hours)

C

n

/ m l

OBSERVEDOBSERVED PREDICTEDPREDICTED

0

20

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100

120

140

160

0 5 10 15 20 25 30

Time (hours)

C p

( n g / m

l )

Calculate absolute % PE on Cmax & AUC:Calculate absolute % PE on Cmax & AUC:(|obs(|obs -- pred| / obs) * 100pred| / obs) * 100


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Evaluation ProceduresEvaluation ProceduresEvaluation ProceduresEvaluation Procedures

Internal predictability:Internal predictability: Based onBased ondata used to define the IVIVCdata used to define the IVIVCmodelmodelExternal predictability:External predictability: Based onBased onadditional test data setsadditional test data sets


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Important considerationsImportant considerationsImportant considerationsImportant considerations

Amount of data used for IVIVCAmount of data used for IVIVCdevelopmentdevelopmentSome combination of 3 or moreSome combination of 3 or moreformulations with adequatelyformulations with adequately

different release rates isdifferent release rates isrecommendedrecommended


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Therapeutic index of drugTherapeutic index of drugTherapeutic index of drugTherapeutic index of drug

Narrow therapeutic index drugNarrow therapeutic index drugInternal and external predictabilityInternal and external predictability

NonNon--narrow therapeutic index drugnarrow therapeutic index drug

Internal predictabilityInternal predictabilityExternal predictability recommended but notExternal predictability recommended but notnecessary if internal pred. criteria are metnecessary if internal pred. criteria are met


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Internal PredictabilityInternal PredictabilityCriteriaCriteria

Internal PredictabilityInternal PredictabilityCriteriaCriteria

% PE% PEabsabs (Cmax and AUC)(Cmax and AUC)Average of 10% or less with none greaterAverage of 10% or less with none greaterthan 15% is acceptablethan 15% is acceptableIf criteria are not met, proceed toIf criteria are not met, proceed to

evaluation of external predictabilityevaluation of external predictability


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External PredictabilityExternal PredictabilityCriteriaCriteria

External PredictabilityExternal PredictabilityCriteriaCriteria

% PEabs (Cmax and AUC)% PEabs (Cmax and AUC)10 % or less is acceptable10 % or less is acceptable1010--20% is inconclusive20% is inconclusiveGreater than 20% is unacceptableGreater than 20% is unacceptable


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PredictionsPredictionsPredictionsPredictions

DissolutionDissolution AbsorptionAbsorption Plasma profilePlasma profile

IVIVC modelIVIVC model PK parametersPK parameters


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0 5 10 15 20 25

Time (hours)

% D

i s s o

l v e

d

0 20 40 60 80 100 120

0

20

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60

80

100

% dissolved

% a

b s o r b e

d

Observed

Predicted

IVIVC model

02040

6080

100120

140160

0 5 10 15 20 25 30

Time (hours)

C

n

/ m l

Cumulative dissCumulative diss

Predicted plasma profilesPredicted plasma profiles

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0 5 10 15 20 25 30

Time (hours)

D i s s o

l u t i o n r a t e

0

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60

80

100

120

0 5 10 15 20 25 30

Time (hours)

A b s o r p

t i o n r a t e

Dissolution rateDissolution rate

Absorption rateAbsorption rate

0

0.2

0.4

0.6

0.8

1

1.2

0 5 10 15 20 25 30

Time (hours)

C

w i t h

1 u

n i t o

f I V

i n


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Evaluation of PredictabilityEvaluation of PredictabilityINTERNALINTERNAL

Evaluation of PredictabilityEvaluation of PredictabilityINTERNALINTERNAL

0 5 10 15 20 25 30

0

20

40

60

80

100

120

TIME IN HOURS

P L A S M A C O N C

. , N G / M L

OBS

PRED

MEDIUM FORMULATION

0 5 10 15 20 25 300

50

100

150

200

TIME IN HOURS

P L A S M A C O N C

. , N G / M L

OBS

PRED

FAST FORMULATION

0 5 10 15 20 25 300

20

40

60

80

TIME IN HOURS

P L A S M A C O N C

. , N G / M L

OBS

PRED

SLOW FORMULATION

%PECmax%PECmax %PEAUC%PEAUCMEDIUMMEDIUM 5.145.14 3.773.77FASTFAST 7.087.08 12.9112.91SLOWSLOW 8.338.33 10.4310.43

Avg.Avg. 6.856.85 9.049.04


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Evaluation of PredictabilityEvaluation of PredictabilityEXTERNALEXTERNAL

%PECmax%PECmax0.110.11

%PEAUC%PEAUC9.79.7

0 5 10 15 20 25 300

50

100

150

200

Time (hours)

P l a s m a C o n c e n t r a

t i o n s

( n g / m

l )

predicted

observed

Predicted plasma concentrations from in vitroEXTERNAL PREDICTABILITY


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Applications of IVIVCApplications of IVIVC


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Ideally, one would like to be able toIdeally, one would like to be able topredict thepredict the in vivoin vivo performance of theperformance of theproductproduct from itsfrom its in vitroin vitro dissolutiondissolution

As a surrogate for bioavailabilityAs a surrogate for bioavailability


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Types of WaiversTypes of Waivers

Waivers for Bioavailability Studies:Waivers for Bioavailability Studies:

Manufacturing site changesManufacturing site changes Equipment changesEquipment changes Method of manufactureMethod of manufacture

Source of raw materialsSource of raw materials Formulation changesFormulation changes


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Criteria for GrantingCriteria for GrantingBiowaivers with an IVIVCBiowaivers with an IVIVC

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120

0 3 6 9 12 16Time (Hours)

%Dissolved

ReferenceTest

0

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100

150

200

Time (hours)

CPReference

Test


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0

100

200

300

400

500

0 10 20 30 40

Time (hours)

C p

( n m o

l / m

l )FastMediumSlowOral Solution


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020

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100

120

0 20 40 60 80 100

% Dissolved

% A

b s o r b e

d


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0

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60

80

100

0 10 20 30

Time (hours)

% D

i s s o

l v e

d

Old FormulationNew Formulation


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ModifiedFormulation

OriginalFormulation

90 % CI

AUC 6129 6073 98-108

CMAX 316 327 93-103

CMIN 160.7 165

TMAX 10.1 6.14

FIss .67 .73


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Level C CorrelationLevel C Correlation

Data obtained from 36 healthyData obtained from 36 healthyvolunteersvolunteers

Eight formulationsEight formulations consisting ofconsisting ofdifferent ratios of slow and fastdifferent ratios of slow and fast

releasing beadsreleasing beads

4 way incomplete block crossover4 way incomplete block crossoverdesigndesignmultiple dose studymultiple dose study


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Relationship between % dissolved atRelationship between % dissolved atvarious times and certain PK parametersvarious times and certain PK parameters

of interestof interest

Parameter Linear CorrelationEquation

Rvalues

Pvalues

AUC

3022.7+(14.32*D6)3041.1+(12.18*D9)3038.47+(11.79*D12)

0.7820.7040.679

0.01100.01540.0171

CMAX

101.8+(4.01*D6)

102.3+(3.5*D9)99.26+(3.43*D12)

0.970

0.9650.967

0.000

0.0000.000


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Dissolution SpecificationsDissolution SpecificationsWith No IVIVCWith No IVIVC

Minimum of 3 points requiredMinimum of 3 points required

Last time point should be the timeLast time point should be the timewhere 80% of claimed labeled amountwhere 80% of claimed labeled amountis dissolvedis dissolved

Specifications set to pass at stage 2 levelSpecifications set to pass at stage 2 levelof testing of the USP acceptance criteriaof testing of the USP acceptance criteria


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Dissolution SpecificationsDissolution Specifications

0

20

40

60

80

100

120

0 3 6 9 12 16

Time (Hours)

%Dissolved

Lower LimitTarget FormulationUpper Limit


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Ideally, all lots within the lower andIdeally, all lots within the lower andupper limit of the specifications areupper limit of the specifications are bioequivalent bioequivalent

Minimally, these lots should beMinimally, these lots should be bioequivalent to the clinical trials lots or bioequivalent to the clinical trials lots oran appropriate reference standardan appropriate reference standard


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Variability should no longer be aVariability should no longer be aprimary considerationprimary consideration

Specifications wider than 20 % areSpecifications wider than 20 % areacceptable only when evidence isacceptable only when evidence issubmitted that lots with meansubmitted that lots with meandissolution profiles that are alloweddissolution profiles that are allowed

by the upper and lower limits are by the upper and lower limits are bioequivalent bioequivalent


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Impart meaning to theImpart meaning to the in vitroin vitrodissolution profiledissolution profile

Justify the specifications and acceptance Justify the specifications and acceptancecriteriacriteria


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Dissolution SpecificationsDissolution Specificationswith IVIVCwith IVIVC

IVIVC should be used to set theIVIVC should be used to set thespecificationspecification

External validation is not required toExternal validation is not required touse the IVIVC for setting specificationsuse the IVIVC for setting specifications

Wider specifications based on what theWider specifications based on what thecorrelation predictscorrelation predicts


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Dissolution SpecificationsDissolution Specificationswith an IVIVCwith an IVIVC

020406080

100120140160

0 3 6 9 1 2 1 5 1 8 2 1 2 4

Time (hours)

CP

LowerLimitUpperLimit

0

20

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60

80

100

120

0 3 6 9 12 16

Time (Hours)

%DissolvedLower Limit

Upper Limit


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Dissolution SpecificationsDissolution Specificationswith a Level C Correlationwith a Level C CorrelationOne time point correlation:One time point correlation:

Use that point to establish the specificationUse that point to establish the specificationin a way that you have a maximumin a way that you have a maximumdifference of 20 % in the mean predicteddifference of 20 % in the mean predicted

CMAX or AUCCMAX or AUC The other points should be no more than 20The other points should be no more than 20

% wide with the clinical/bio profile% wide with the clinical/bio profileconsidered to be the target profile toconsidered to be the target profile toachieveachieve


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Dissolution SpecificationsDissolution Specificationswith a Level C Correlationwith a Level C CorrelationMultiple Level C Correlation:Multiple Level C Correlation: establish specifications at each time pointestablish specifications at each time point

in a way to have a maximum difference ofin a way to have a maximum difference of20 % in the mean predicted CMAX or AUC20 % in the mean predicted CMAX or AUCwhichever is tighterwhichever is tighter


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Release Rate SpecificationsRelease Rate Specifications

If the release characteristics of theIf the release characteristics of theformulation can be described by a zeroformulation can be described by a zeroorder for some period of time and theorder for some period of time and thedissolution profile appears to fit a lineardissolution profile appears to fit a linearfunction over that time thenfunction over that time then

A release rate specification to describe theA release rate specification to describe thedissolution characteristics could bedissolution characteristics could beestablishedestablished


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Zero Order Release RateZero Order Release Rate

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0 5 10 15 20 25

Time (hours)

% D

i s s o

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d


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Release Rate SpecificationRelease Rate Specification

0

20

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60

80

100

120

0 2 4 6 8 12 16 20 24

Time (hours)

% Diss

6.2 upper9.4 upperLower limitUpper limit

00.5

11.5

22.5

33.5

4

0 2 4 6 8 12 16 20 24

XTime (hours)

Cp 6.2 upper

9.4 upper


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Release Rate SpecificationRelease Rate Specification

0

20

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60

80

100

120

0 2 4 6 8 12 16 20 24Time(hours)

% diss

9.4 lower9.4 upperLower limitUpper limit

00.51

1.52

2.53

3.54

0 2 4 6 8 12 16 20 24Time (hours)

Cp 9.4 lower9.4 upper


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Level A Correlation notLevel A Correlation notInvolving DeconvolutionInvolving Deconvolution

Correlation was obtained from in vivoCorrelation was obtained from in vivodata obtained from 6 different studiesdata obtained from 6 different studies

Media Consisted of PH 1.5 for the firstMedia Consisted of PH 1.5 for the first1.5 hours then PH 6.8 buffer for the1.5 hours then PH 6.8 buffer for theremainder of the 24 hoursremainder of the 24 hours


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Input FunctionInput Function

WEIBULL FUNCTION:WEIBULL FUNCTION:

Ft= Dose(1Ft= Dose(1--expexp--((t((t--tl)/td)^beta)tl)/td)^beta)where Dose= labelled dose.where Dose= labelled dose.

t and tl time and lag time for dissolution.t and tl time and lag time for dissolution.td= time required for 63.2 % of the drugtd= time required for 63.2 % of the drugto dissolve.to dissolve. beta= unitless number ranging from 0 to1. beta= unitless number ranging from 0 to1.


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Plasma Profile ObservedPlasma Profile ObservedAnd Predicted fromAnd Predicted from

DissolutionDissolution


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Dissolution LimitsDissolution Limits


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Predicted Plasma ProfilesPredicted Plasma ProfilesFor the Upper and LowerFor the Upper and Lower

SpecificationSpecification

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