How Can IVIVC/IVIVR Be Used?

James E. Polli

jpolli@rx.umaryland.edu

September 6, 2012

Outline

• General considerations • Recommended method

– A IVIVR method is recommended to characterize the contributions of each dissolution and permeation to overall drug absorption kinetics. The method addresses biopharmaceutic risk.

– Polli, J.E., Crison, J.R., and Amidon, G.L. (1996): A novel approach to the analysis of in vitro-in vivo relationships. J. Pharm. Sci. 85:753-760.

– Polli, J.E., Rekhi, G.S., Augsburger. L.L., and Shah, V.P. (1997): Methods to compare dissolution profiles and a rationale for wide dissolution specifications for metoprolol tartrate tablets. J. Pharm. Sci. 86:690-700.

– Polli, J.E.:“In Vitro-In Vivo Relationships of Several “Immediate” Release Tablets Containing a Low Permeability Drug”. In Young, D., Devane, J.G. and Butler, J. (eds.), In Vitro-In Vivo Relationships; Plenum: New York, 1997, pp. 191-199.

– Polli, J.E. and Ginski, M.J. (1998): Human drug absorption kinetics and comparison to Caco-2 monolayer permeabilities. Pharm. Res. 15:47-52.

– Polli, J.E. IVIVR vs. IVIVC. (2000): Dissolution Technologies 7(3): 6-16.

Biopharmaceutic Risk

• For a SUPAC change, a IR tablet of a BCS Class 2 drug demonstrates rapid in vitro dissolution (including being in spec). Is a biowaiver possible?

• For a SUPAC change, a ER tablet of a BCS Class 2 drug demonstrates in vitro dissolution in spec. Is a biowaiver possible?

Biopharmaceutic Risk

• What type of drug product would you be most comfortable developing if you could only rely on in vitro dissolution as the key pharmacokinetic/biopharmaceutic test (i.e. not rely on in vivo pharmacokinetic testing)?

Biopharmaceutic Risk

• For an IR product, in what way is it desirable that in vivo dissolution be the rate-limiting step for drug absorption?

• For an IR product, is there any advantage for in vivo dissolution to not be the rate-limiting step for drug absorption?

• If in vivo dissolution is not-limiting for drug absorption, and in vitro dissolution exactly measures in vivo dissolution, what would be the relationship between dissolution and absorption?

ACPS-CP Meeting on Aug 8, 2012

• Question to Advisory Committee for Pharmaceutical Science and Clinical Pharmacology (ACPS-CP)

• What methods do you recommend FDA consider in order to develop a mechanistic understanding of the relationship between in vitro dissolution and in vivo performance?

Categories of IVIVC/IVIVR

• Convolution (FDA Level A) AAA

• Deconvolution AA

• Deconvolution (but only linear) A

– USP Level A

• Summary parameters B

• Point estimates C

• Rank order D

Polli, J.E. “Analysis of In Vitro - In Vivo Data”. In Amidon, G.L., Robinson, J.R., and Williams, R.L. (eds.), Scientific Foundation and Applications for the Biopharmaceutics Classification System and In Vitro - In Vivo Correlations; AAPS Press: Alexandria, VA, 1997, pp. 335-352.

Selection of IVIVC Approach

interested in drug absorption

interested in overall pharmacokinetics

Level AA (deconvolution-based)

Level AAA (convolution-based)

Deconvolution IVIVR

• Application of the nonlinear, deconvolution-based model to the in vitro-in vivo relationships

– metoprolol

– piroxicam

– ranitidine

• Hypothesis: Factor(s) controlling overall absorption kinetics and dosage form performance can be elucidated from IVIVR.

• Only requires one formulation.

• Early formulation development.

dd

a

a FFf

F 11

11

11

1

Model Development

solid dosage form

solution in GIT

drug in plasma

dissolution

permeation

Model Development

dissolution absorption

time

Model

• Fa is the fraction of the total amount of drug absorbed at time t,

• fa is the fraction of the dose absorbed at t = infinity, • alpha is the ratio of the first-order apparent permeation

rate coefficient (kpapp) to the first-order dissolution rate

coefficient (kd), and • Fd is the fraction of drug dose dissolved at time t. • Polli, J.E., Crison, J.R., and Amidon, G.L. (1996): A novel

approach to the analysis of in vitro-in vivo relationships. J. Pharm. Sci. 85:753-760

dd

a

a FFf

F 11

11

11

1

Model Assumptions

• Only dissolution and permeation

– first-order dissolution (kd)

• Fdin vitro = Fd

in vivo = Fd

– first-order permeation (kp)

• Assumptions in the determination of Fa

Alpha

• large alpha: dissolution rate-limited absorption

• small alpha: permeation rate-limited absorption

• alpha = 1: mixed rate-limited absorption

d

app

p

k

k

Theoretical IVIVRs

dd

a

a FFf

F 11

11

11

1

0 .0

0 .5

1 .0

0 0 .2 5 0 .5 0 .7 5 1

fra c tion dis s olve d

fra

cti

on

ab

so

rbe

d

1 0 0

1 0

5

2

1 .0 1

0 .5

0 .2

0 .1

0 .0 1

USP Level A

• USP Level A is a special (linear) case of

where fa = 1 and >>1, such that Fa = Fd.

dd

a

a FFf

F 11

11

11

1

Reasons for Unsuccessful “In Vitro - In Vivo Correlation”

• inadequate “IVIVR” model – in vivo dissolution not rate limiting

• in vitro dissolution did not replicate in vivo dissolution – dissolution is being used as a QC tool

• challenges with in vivo study design/conditions – variability/power

– drug PK

Obervations from Historical “Straight Line” Correlations

• Need dissolution to be rate-controlling

• Generally require the same mechanism in order to observe the same “correlation” pattern

• Different mechanism generally result in different “correlation” pattern

Correlation

• “degree of relationship between two random variables”

Kachigan, S.K. Multivariate Statistical Analysis; Radius Press, New York, 1991.

Deconvolution IVIVR Model

solid dosage form

solution in GIT

drug in plasma

dissolution

permeation

dd

a

a FFf

F 11

11

11

1

Effect of Incomplete Absorption due to Low Permeability

• Plasma data over-estimates absorption kinetics, since it does not “see” unabsorbed drug.

• Polli, J.E. and Ginski, M.J. (1998): Human drug absorption kinetics and comparison to Caco-2 monolayer permeabilities. Pharm. Res. 15:47-52.

permeation

Metoprolol Dissolution Profiles

f2 = 19.1 m = 0.80

0

20

40

60

80

100

120

0 20 40 60 80 100 120

time (min)

perc

en

t d

iss

olv

ed

Lopressor

fast

medium

slow

Metoprolol Plasma Profiles

0

20

40

60

80

100

0 4 8 12 16 20 24

time (hr)

me

top

rolo

l p

lasm

a

con

ce

ntr

ati

on

(ng

/ml)

Lopressor

fast

medium

slow

Metoprolol IVIVRs

0

0.2

0.4

0.6

0.8

1

0 0.2 0.4 0.6 0.8 1

fraction metoprolol dissolved

fra

cti

on m

eto

pro

lol

abs

orb

ed

Lopressor

fast

medium

slow

Metoprolol Absorption Kinetics

fa

alpha

kd

(hr-1

)

kpapp

(hr-1

)

twin

(hr-1

)

phi

kp

(hr-1

) Lopressor 0.923

(0.025)

0.0877

(0.0328)

9.24

(0.12)

0.810

(0.268)

1.89

(0.16)

0.852

(0.063)

0.648

(0.248)

Fast 0.962

(0.024)

0.0743

(0.0178)

8.34

(0.48)

0.619

(0.139)

2.25

(0.56)

0.930

(0.042)

0.591

(0.138)

Medium 0.882

(0.034)

0.0995

(0.0181)

4.02

(0.17)

0.400

(0.068)

1.88

(0.26)

0.846

(0.045)

0.330

(0.048)

Slow 0.885

(0.030)

0.648

(0.103)

1.63

(0.11)

1.05

(0.16)

2.67

(0.36)

0.736

(0.066)

0.778

(0.153)

Mean 0.910

(0.015)

- - 0.759

(0.098)

2.22

(0.18)

0.830

(0.031)

0.609

(0.085)

Polli, J.E., Rekhi, G.S., Augsburger. L.L., and Shah, V.P. (1997): Methods to compare dissolution profiles and a rationale for wide dissolution specifications for metoprolol tartrate tablets. J. Pharm. Sci. 86:690-700.

Hypothesis

• Modest changes in dissolution have no in vivo consequence for IR dosage forms whose overall absorption is not dissolution controlled.

– When can bioequivalence studies be waived for IR products that exhibit modest differences in dissolution?

– Is a dissolution method acceptable if two IR products are bioequivalent, but exhibit modest differences in dissolution?

Piroxicam Dissolution Profiles

f2 = 23.4 m = 0.66

0

20

40

60

80

100

0 20 40 60 80 100 120

time (min)

perc

en

t d

iss

olv

ed

Feldene

fast

medium

slow

Piroxicam Plasma Profiles

Piroxicam IVIVRs

0

0.2

0.4

0.6

0.8

1

1.2

0 0.2 0.4 0.6 0.8 1

fraction piroxicam dissolved

fra

cti

on p

iro

xic

am

abs

orb

ed Feldene

fast

medium

slow

Piroxicam Absorption Kinetics

fa alpha kd

(hr-1

)

kpapp

= kp

(hr-1

)

Fast 0.949

(0.018)

0.896

(0.138)

8.10

(0.60)

7.26

(1.12)

Medium 0.893

(0.020)

1.54

(0.24)

4.66

(0.10)

7.17

(1.10)

Feldene 0.896

(0.019)

3.42

(0.84)

3.13

(0.20)

10.7

(2.6)

Slow 0.819

(0.022)

6.50

(2.17)

1.75

(0.05)

11.3

(3.8)

Mean 0.892

(0.011)

- - 9.00

(1.14)

Polli, J.E. and Ginski, M.J. (1998): Human drug absorption kinetics and comparison to Caco-2 monolayer permeabilities. Pharm. Res. 15:47-52

Ranitidine Dissolution Profiles

f2 = 32.1 m = 0.44

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40 45

time (min)

perc

en

t d

iss

olv

ed

Zantac

fast

medium

slow

Ranitidine Plasma Profiles

Ranitidine IVIVRs

0

0.2

0.4

0.6

0.8

1

1.2

0 0.2 0.4 0.6 0.8 1

fraction ranitidine dissolved

fra

cti

on r

an

itid

ine

abs

orb

ed

Zantac

fast

medium

slow

Ranitidine Absorption Kinetics

fa

alpha

kd

(hr-1

)

kpapp

(hr-1

)

twin

(hr-1

)

phi

kp

(hr-1

)

Fast 0.502

(0.018)

0.0646

(0.0095)

10.4

(1.4)

0.680

(0.095)

2.00

(0.17)

0.361

(0.19)

0.113

(0.030)

Zantac 0.520

(0.016)

0.0943

(0.0181)

6.18

(0.30)

0.583

(0.108)

2.10

(0.20)

0.399

(0.10)

0.227

(0.041)

Mediam 0.541

(0.016)

0.0964

(0.0194)

5.33

(0.29)

0.514

(0.100)

2.50

(0.34)

0.419

(0.18)

0.206

(0.036)

Slow 0.517

(0.021)

0.156

(0.020)

3.94

(0.64)

0.613

(0.075)

2.14

(0.16)

0.374

(0.13)

0.233

(0.031)

Mean 0.520

(0.009)

- - 0.597

(0.047)

2.18

(0.12)

0.389

(0.009)

0.225

(0.017)

IVIVR Analysis and Permeability

drug P (cm/sec)

x 106

kp (pred)

(hr-1)

kp (obs)

(hr-1)

piroxicam 91.3

( 1.2)

3.49

( 0.05)

9.00

( 1.14)

metoprolol 10.7

( 0.3)

0.410

( 0.011)

0.609

( 0.085)

ranitidine 0.425

( 0.058)

0.0163

( 0.0022)

0.225

( 0.017)

Summary

• The factor(s) controlling overall absorption kinetics and dosage form performance can be elucidated from in vitro dissolution - in vivo absorption relationships.

– kinetic importance of dissolution

– f2 criteria (or other metrics)

– connection to Caco-2 permeability