Use of IVIVc and IVIVe to support formulation development ... · IVIVe vs IVIVc In vitro- in vivo...

| 1 Xavier Pepin – AAPS meeting 4th Nov 2014

Use of IVIVc and IVIVe to support formulation development Industrial case studies

Dr. Xavier Pepin, Global Head of Biopharmacy, Pharmaceutical Sciences and Operations, Sanofi R&D

AAPS meeting– 4th November 2014


Outline of the presentation

● Some definitions

● Contribution of Biopharmacy along the

industrial affair value chain

● 4 case studies with successful application of IVIVe

● 1 case study where PBPK models cannot be used

(today)


IVIVe vs IVIVc

● In vitro- in vivo correlations (IVIVc)

● Mathematical models relating the in vitro behavior of drug

products and their bioavailability

• Regulatory tool used to support changes

• Valid for one dose, one species, one dissolution method

and formulations comprised between the extremes tested

• Different levels to the correlations

• Useful for modified release BCS I and some BCS II with

caution


IVIVe vs IVIVc

● In vitro in vivo extrapolations (IVIVe)

● In vitro dissolution are used to calculate in vivo release in a in

silico PBPK tool representing the human physiology.

• Other factors are considered such as transit, solubility,

permeability, precipitation, degradation, local pH…

• Much more reliable model can be built with IR formulation and

applied to MR, in vitro methods can be used as input,

extrapolations can be done

• Not yet a regulatory tool but can be accepted to waive BE

studies under certain cases


Biopharmaceutical models use along IA value chain

Target drug product profile

Prototyping Bioequivalence

study Dossier

du

e

Dilig

en

ce

Ideation-Feasibility

• LCM : Dose and release

profile to reach target

exposure/efficacy

• Definition of drug property

thresholds

• Generics/LCM : Dissolution

range for bioequivalence

Contribution to prototype selection

• Anticipation of bioequivalence/superiority

to reference product

Biowaivers

• Use of IVIVe to support

formulation/process

changes in the absence of

guidance

Trouble-shooting

• Understand failure reasons

Drugability

• Main sources of variability

• Formulation robustness

evaluation

• Risk assessment

Case study #1

Case study #2 Case study #3

Case study #4


Case study #1

Paracetamol “night” Define release rate and administration time

to achieve maximum pain relief during the

night for a 1 g tablet

http://dysfunctionaldraught.deviantart.com/art/Night-sky-sketch-287032005


PK/PD relationship Biopharmaceutical properties

● Physico-chemical properties

● pKa: 9.5 (25°C, acid)

● Log P: around 0.3 - 0.2

● Solubility = 23.7 mg/mL at 37°C (no pH dependence)

● Permeability = CaCo2 cells ~ 300 10-7 cm/sec

● Short half life in man (2-3 hours)

● Efficacy : Central

1: Van der Marel C.D. et al., Acetaminophen in cerebrospinal fluid in children, Eur J Clin Pharmacol (2003) 59: 297–302

2: Bannwarth B. et al., Plasma and cerebrospinal fluid concentrations of paracetamol after a single intravenous dose of

propacetamol, Br. J. clin. Pharmac. (1992), 34, 79-81

Distribution model

CSF/Plasma 1

PK in adults

plasma + CSF2

http://scientifique.sanofi-aventis.com/Pages/fr/Presentation/nominations.htm?opening=menu_1_2


PK/PD relationship

● Acute pain (dental surgery)

Direct PK/PD using CSF concentrations

CCSF Thresholds were defined :

4 µg/mL for chronic and 5µg/mL for acute pain

Efficacy vs Cp 1

Efficacy vs CCSF

1 : R. A. Seymour and M. D. Rawlins, Pharmacokinetics of

Parenteral Paracetamol and its Analgesic Effects in Post-

Operative Dental Pain, Eur J Clin Pharmacol (1981) 20:215-

218

Calculation of CCSF

http://scientifique.sanofi-aventis.com/Pages/fr/Presentation/nominations.htm?opening=menu_1_2


Paracetamol : GastroPlus model PK building

● PK model building

● Use of Measured IR oral or IV PK profiles1,2

to fit Vd, k12 k21 and clearance

1 : Rawlins and al., Pharmacokinetics of paracetamol after intravenous and oral

administration, Eur. Clin. Journal of Pharmacology, 283-286, 1977.

2 : Borin M.T. et al., Single dose bioavailability of Acetaminophen following oral

administration IJP 54 (1989) 199-209


Paracetamol LP GastroPlus model PK validation (1/2)

● PK model Validation

● Use of Tylenol in vitro dissolution3 & in vivo PK profiles 3,4 to estimate model validity

3: Journal of Controlled Release 108 (2005) 351–361

4: Int. J. of Current Pharm. Res. 2(4) (2010) 28-31

Use of Weibull

equation to fit

vitro data


Paracetamol LP GastroPlus model PK validation (2/2)

● PK model Validation : Direct IVIVe

3: Journal of Controlled Release 108 (2005) 351–361

4: Int. J. of Current Pharm. Res. 2(4) (2010) 28-31

Parameter Unit Value

Peff human 10^-4 cm/s 7

Vd L/kg 0.44

CLT L/h/kg 0.28

Ratio blood/plasma / 1.2

Liver first pass % 18.093

Adequate anticipation of

PK profile Model

usable


Paracetamol LP Use of model

● Chronic pain : Define optimal release rate

● Plasma concentrations transformed in CSF concentrations

1 g IR at wake up (08h00), 1g IR at lunch

(14h00), 1g IR at bed-time (22h00)

1 g IR at wake up (08h00), 1g IR at lunch

(14h00), 1g MR at bed-time (22h00)

Gain of 1 hour analgesia at the

same dose with MR formulation


Case study #2

Zolpidem ODT Define bioequivalent dissolution range for

immediate release Zolpidem products


Zolpidem hemitartrate– Physico-chemical and biopharmaceutical properties

● MW = 764.88 g.mol-1 (=307.4 for active moiety)

● Salt to base ratio = 1.24

● CaCo2 Papp = 465 10-7 cm/s

● scaled to human jejunal Peff = 8,14 10-4cm/s

● fu,p = 7.5%, B:P = 0.76 1

● Weak base

● pKa = 6.18

● Aqueous solubility

● pH dependent

0.2 mg/mL @ pH 6.8

● Questions to Biopharm

● Can the ODT formulation be bioequivalent to the reference IR tablet despite

dissolution differences ?

12,5 mg products are

BCS class I

1: DMD 27(11) 19991350-1359


Human data – Building up a GastroPlus model

● In vivo PK data exist for

● 8 mg zolpidem IV bolus,

● IR formulations at 2.5, 5, 7.5, and 10 mg zolpidem hemitartrate

● MR formulations at 10 mg and 12.5 mg Zolpidem hemitartrate

● Strategy : Use IV data and check model on IR and MR product

● IR : Let G+ calculate the in vivo dissolution

● MR : use direct IVIVe

1: DRUG METABOLISM REVIEWS. 24(2). 239-266 (1992)

One compartment PK model in

agreement with literature1


Verification on oral IR products

Good fit of IR profiles in

caucasians

Good fit of IR profiles in

japanese


Model performance on “modified release” formulation

● Purpose : Investigate model performance on modified

release and a potential in vitro in vivo extrapolation

● Zolpidem is a BCS class I drug and therefore any

modification of the release rate could impact the profile

● Use of 10 mg MR & 12.5 MR formulation (AMBIEN CR), pH

6.8 900mL dissolution profile.

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7

% r

ele

ased

Time (H)

Good estimation of

tmax, Cmax and AUC with a direct IVIVe


Sensitivity analysis

● Stomach transit time

● Major reduction on Cmax and increase in tmax

● No anticipated effect on AUC


Dissolution Profile - Buffer pH 6.8 - 1T023

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70

time (min)

% d

iss

olv

ed

1T023 pH=6.8 50rpm

Anticipation of ODT behaviour using GastroPlus

● Using an ODT batch dissolution profile representative of the BE study

0

10

20

30

40

50

60

70

0 2 4 6 8 10 12 14 16 18

Time (H)

Cp

lasm

a (

ng

/mL

)

Cp-Zolpidem 5mg IR (ng/mL)

Cp-ODT 5 mg 1T023 (µg/mL)

Batch 1T023

Ratios ODT/IR

Good chance of being bioequivalent

despite differences in dissolution


Definition of bioequivalent space

● Target for 5 mg dose IR

● Cmax = 0,67 µg/mL, AUC inf = 293 ng.h/mL, tmax = 1 h

● Variation in stomach transit time alone can lead to large

Cmax variability (fasted state)

Cmax (µg/mL)

Stomach transit time (h)

0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0

Weib

ull

tim

e s

cale

(h)

0,2

0,4

0,6

0,8

1,0

1,2

1,4

1,6

1,8

2,0

0,040

0,040

0,045 0,045

0,045

0,045

0,045

0,0500,050

0,050

0,050

0,055

0,055

0,055

0,060

0,060

0,065

Tmax (h)


0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0

Weib

ull

tim

e s

cale

(h)

0,2

0,4

0,6

0,8

1,0

1,2

1,4

1,6

1,8

2,0

4,0

3,5

3,5

3,0

3,0

3,0

3,0

2,5

2,5

2,5

2,5

2,0

2,0

2,0

1,5

1,51,0

AUC inf (ng.h/mL)


0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0

Weib

ull

tim

e s

cale

(h)

0,2

0,4

0,6

0,8

1,0

1,2

1,4

1,6

1,8

2,0

291,0

291,0

291,0

291,0

291,5

291,5

291,5

291,5

292,0

292,0

292,0

292,0

292,5292,5

292,5

292,5

290,5

290,5

290,5290,0

289,5

Test A=0.17h

Ref A = 0.01H BE space is large enough compared to

test and reference formulations


Case study #3

Diltiazem MR Transfer from plant A to plant B of a modified

release product, BEQ failed despite

comparable dissolution using QC method.

Can we understand and make

recommendation for future BE study ?


Diltiazem extended release Transfer from plant A to plant B

● Extended release formulation of diltiazem comprising a mixture of IR and MR pellets

● MR technology : coating with Eudragit RS/RL polymer

● BE study failed on Cmax

● In vitro pH 1 data

● Slight difference but within specs

● Question to Biopharmacy

● Why did the BE study fail ?

● Can we avoid similar failures in the future ?

B/A Cmax

0.84 [0.78-0.90]

B/A AUC0-∞

0.94 [0.88-0.99]


Diltiazem Biopharmaceutical properties

● Phys-chem properties

● Log P = 2.89

● pKa 8.02 (Base)

● Permeability

• Scaled from Caco2 data

Compartment pH fasted Papp fasted Peff fasted pH fed Papp fed Peff fed

Stomach 1.3 4.9

Duodenum 6 119.2 3.35 5.4 29.8 1.40

Jejunum 1 6.2 149 3.86 5.4 29.8 1.40

Jejunum 2 6.4 178.8 4.35 6 119.2 3.35

Ileum 1 6.6 208.6 4.81 6.6 208.6 4.81

Ileum 2 6.9 253.3 5.46 6.9 253.3 5.46

Ileum 3 7.4 327.8 6.47 7.4 327.8 6.47

Caecum 6.4 178.8 4.35 6.4 178.8 4.35

Asc Colon 6.8 238.4 5.25 6.8 238.4 5.25

European Journal of Pharmaceutical Sciences 24 (2005) 333–349

European Journal of Pharmaceutical Sciences, 14, 281 –291 (2001)

Pharmaceutical Research, 14(9), 1210-1215, (1997)

Good solubility and permeability down

to the lower sections of the GI tract


Methodology : top-down analysis using PBPK tools

● Fit of plant A PK data to extract in vivo release profile using 2-phase

Weibull equation and GastroPlus ® In vivo

In vitro pH 1

Significantly quicker in vivo dissolution

compared to that measured at pH1


Diltiazem extended release IVIVe with pH 1 data

In vivo dissolution is ~6h quicker

than in vitro dissolution


Diltiazem extended release IVIVe with pH 1 data

Reasons for failure

Eudragit RS/RL contains chloride anions.

0

5

10

15

20

25

30

35

40

45

NaCl NaH2PO4,

2H2O

HCl Water

% w

/w incre

ase o

f E

udra

git R

S f

ilm

Average hydration % w /w @ t=5hAverage hydration % w /w @ t=125h

active

Eudragit® RS/RL pH independent prolonged release

Sugar pellet

Reduced Eudragit RS film

hydration in the presence of Cl-

Recommendation to use pH 6.8

phosphate buffer w/o chloride

HCl 0.1 M not adapted !


Diltiazem extended release IVIVe with pH 6.8 data

Adequate IVIVe using pH 6.8 data

The reason for BE study failure is that products were different

New pH 6.8 dissolution method more discriminating

New pH 6.8 dissolution method is more representative & can be

used to screen future batches for BE testing


Diltiazem extended release Impact of gender on BE study

4H more transit time per large intestinal segments

for females vs males a

• Males CTT estimated at 12h

• Females CTT from 16h to 20h

a: http://www.icrp.org/publication.asp?id=ICRP%20Publication%20110

Majority of the drug absorbed at

ICJ and ascending colon

Longer transit times in

lower intestine could

explain female larger

exposure

CTT = Colon Transit Time


Case study #4

Felodipine ER Development of a biowaiver in support of

site manufacturing change (Astra-Zeneca,

Sweden to Zentiva, Turkey)


Felodipine Biopharmaceutical properties

● Permeability 1

● Caco2 : 42 10-7 cm/s

● No polarity of transport

● Scaled to human jejunal Peff = 1,73 10-4 cm/s

● Precipitation from super-saturated solutions 2

● In the presence of HPMC or HPMC-AS drug stays super-saturated for 3 hours

High permeability

Tp = 140 to 2000 seconds

1: DMD 38:1147–1158, 2010

2: European Journal of Pharmaceutics and Biopharmaceutics 70 (2008) 493–499


Felodipine Biopharmaceutical properties

● Phys-chem & biopharm properties 1

● Clinical dose : 2.5 & 5 mg

● Log P = 5.58, MP = 146 celcius

● No pKa in physiological range

● Fu,p = 0.4%, B:P = 0.7

● Low aqueous solubility (0,9-1,2µg/mL)

● Impact of surfactants on solubility

European Journal of Pharmaceutics and Biopharmaceutics 64 (2), 2006, 200–205

DMD 38:1147–1158, 2010

International Journal of Pharmaceutics 405 (2011) 79–89

Pharmaceutical Research 11 (8) 1994 1093-1097

Low solubility (BCS II)

Medium chosen for in vitro drug

product dissolution (CTAB 0,4%)

SDS discarded due to interaction

with matrix

Physiological surfactants


Felodipine – GastroPlus model building

● Full PBPK model

● Human American male of 32y/o + 73 kg



● ACAT model

● Amount of fluid reduced to 7,5% and 2% in SI and colon

match the free liquid volume measured by Schiller1 (MRI)

1 : Aliment. Pharmacol. Ther 2005, 22, 971-979



● Estimation of clearance

● Liver & gut tissue

● Use of Km and Vmax values + intrinsinc human liver clearance measured

in vitro for felodipine isomers 1,2

● Model verification on IV and oral solutions 3

1: Drug metabolism and disposition 19(5) 1991 889-894

2: Current Drug Metabolism 8(7) 2007, 679-684

3: BIOPHARMACEUTICS & DRUG DISPOSITION, VOL. 8, 235-248 (1987)


Goodness of fit – oral solutions

● Model considered adequate for IR products

Acceptable anticipation of

Cmax and AUC


In vitro – In vivo extrapolation for MR formulations

● Use of literature data from Wingstrand K.et al. 1 and Abrahamson B. et al.2

● In vitro and in vivo data for extended release products

● Use of in vitro release data (using dossier method)

● USP2, 500 mL 0.1M phosphate medium pH6.5 with 0.4% CTAB, 37°C, 100 rpm

● 3 batches with different release rates (tablet A, B and C)

● Level B correlation already demonstrated by Astra Zeneca (part of the dossier)

● In GastroPlus : Switch formulation as controlled release “integral tablet”

● Use of in vitro as direct input for IVIVe

1 : International Journal of Pharmaceutics, 60 (1990) 151-156

2: Pharmaceutical research 11(8) 1994 1093-1097


Felodipine tablet A Direct IVIVe

● Use of the Weibull 2 phase function to fit in vitro data

● In vitro in vivo


Felodipine tablet B Direct IVIVe




Felodipine tablet C Direct IVIVe



Almost complete metabolism

of fraction absorbed upper GI


Felodipine tablet A Use of PK profile to fit in “vivo dissolution”

● In vivo in vitro

Nice match of the first 2,5 hours release

In vivo release more complete than in vitro ?


Felodipine tablet B Use of PK profile to fit in “vivo dissolution”

● In vivo in vitro

Nice match of the first 4 hours release

In vivo release more complete than in vitro ?


Felodipine tablet C Use of PK profile to fit in “vivo dissolution”

● In vivo in vitro In vivo release more complete than in vitro ?


Felodipine tablet C Use of PK profile to fit in “vivo dissolution”

● Hump in the PK profile

● ASF model Optimal Log G SA/V 6.1

boost lipophilic drug absorption from

lower segments of GI tract 1

1:Advanced Drug delivery reviews 50 2001, S41-S67

Effect could also be related to

mechanical stress on the

hydrophilic matrix upon large

colon arrival & food intake


Level A IVIVc

● 3 types of formulations

● Good correlation with release from 2-5H

● Later time points

• In vivo > In vitro Higher permeability or higher disintegration ?

Overall Level A correlation considered

adequate to waive manufacturing site change

(same formulation, same dissolution)


Case study #5

Darifenacin 15 mg ER Generic formulation development

Impact of physiology on model construction

http://www.aimgroup.eu/assets/images/logo-zentiva.jpg


Darifenacin.HBr Biopharmaceutical properties 1

● C28H30N2O2 . HBr

● pKa = 9.2 (base)

● MW = 507.5 (base 426.55)

● Log P = 3.621

● fu,p = 2%

● B:P = 0.68

● CYP2D6 & CYP3A4 hepatic

and intestinal metabolism

● Fa ~ 97%

● Caco2 data

● Papp A2B = 19 10-6cm/s

● Papp B2A = 22 10-6 cm/s

● Clinical dose = 15 mg, extended release product (hydrophilic matrix)

Medium pH Solubility, Cs

[mg/ml]

0.1M HCl 1.0 4.5

0.01M HCl 2.0 4.7

Acetate buffer 4.5 5.1

Phosphate buffer 6.8 4.9

Water - 4.5

BCS class I – MR product

1 : Clin Pharmacokinet 2006; 45 (4): 325-350


Generic formulation development Reference = Emselex 15mg

● Prolonged release matrix tablet (20-24H)

Dissolution Parameters:

Apparatus Apparatus I (Basket)

Temperature 37 ± 0.5 °C

Rotation Speed 100

Volume 900 ml

Good profile similarity but

Difference @ pH 6.8 ∆t50% = 2.2h


Darifenacin 15 mg vs. Emselex 15 mg BE study

● Fed state, cross over, healtly volunteers

● Randomized and dosed 56 (23 females and 33 males), completed 53

● Darifenacin 15 mg (Test) vs Emselex 15 mg (Ref)

BE successful


Building the GastroPlus model

● Compartmental approach

● Use of literature IV data

calculate 3 compartment model

● Direct application of this model for oral

• Fixed liver FPE of 63%


Direct IVIVe with Darifenacin pH 6.8 data

● Use of the Weibull single phase function as input

Overestimation of

PK from 10 hours



● Dissolution of the tablet in the lower segments of the GI tract

Majority of the drug

absorbed from the

lower segments



● Reduction of ASF factors in the colon to 0.2

● Incomplete dissolution Let weibull fit to max 92% released ?

● Metabolic degradation due to microflora ?

Better data match


Direct IVIVe with Emselex pH 6.8 data

● Using adjustment of ASF as for the Test product

● Dissolution complete for this drug product

Under-estimation

What’s wrong ?


Use of average profiles ?

● Large variability observed for both test and reference products

● In vitro dissolution compatible with observed PK ?

Large variability in the human PK

with both ref and test

Meaning of average Cp(t) profile ?


Cp time profiles for individual subjects

● Peaks and troughs in the PK profiles


Cp time profiles for individual subjects

● Peaks and troughs in the PK profiles


Darifenacin : Peaks in the PK profiles

● Potential causes multiple peaks 1

● Enterohepatic recirculation

• Only in case of food administration (not before 4 hours in fasted clinical

trials)

● Salivary –Enteric recirculation

● Site specific absorption

● Gastric motility

• Highly permeable and soluble drugs, i.e. markers of gastric emptying

● Other causes

● Colon peristalsis matrix degradation

● Presence of microflora matrix degradation ?

● Darifenacin ER peaks in the fed state PK profiles

● Most frequent 4 hours (emptying), 8-10 hours (food), 20 hours post

administration (following morning)

● Not systematic for Test and Ref, not formulation related

● Not seen by IV route

1: Clin Pharmacokinet 2010; 49 (6): 351-377

Except for 4-6 hour time peak (gastric emptying)


Impact of free water volume, hydrodynamics, hydrostatic pressure on release ?

● Meals and waking increase peristalsis and intraluminal pressure in the

colon

1:S.S.C. Rao et al., Am. J. Gastroenterology, 99 (2004) 2405-2416

From S. Rao et al.1

Basket

100 rpm

86 min


Analysis of individual profiles for 20 subjects

● Modeling of individual PK data

● 2 compartment disposition model

● Fractional doses (up to 4)

Fit of V/F, k, k12, k21, Di, tDi, kai

Keeping V/F, k, k12, k21 constant for Ref and Test



● Calculation of in vivo absorption

● Using previous parameters

● Comparison of in vivo absorption to in vitro dissolution

%𝐴𝑏𝑠 = 100 × 𝐷𝑖 1 − 𝑒

−𝑘𝑎𝑖 𝑡−𝑡𝐷𝑖𝑛𝑖=1

𝐷



● Calculation of in vivo absorption

● Using previous parameters

● Comparison of in vivo absorption to in vitro dissolution

%𝐴𝑏𝑠 = 100 × 𝐷𝑖 1 − 𝑒

−𝑘𝑎𝑖 𝑡−𝑡𝐷𝑖𝑛𝑖=1

𝐷

+/- marked phases in the in vivo absorption


In vitro vs in vivo (average +/- SD)

Darifenacin

Emselex

Overall agreement between in vitro

(n=12) and in vivo (n=20) for both

formulations

y=x

y=x


In vitro vs in vivo (average +/- SD)

Large Tmax range owing to multiple peaks

Darifenacin dissolves more rapidly than Emselex

which shows in vivo after stomach emptying

No appreciable impact on Cmax (T/R=1.1 or

AUC (T/R=1)

Current limitation of PBPK tools

Stomach not

emptied

y=x


Conclusions - Perspectives

● IVIVc/IVIVe are useful in LCM, generic and NCE commercial formulation

development

Material screening (prototypical dosage forms, due

diligence)

Material definition (type of DP, target DP release rate or

location) to maximize efficacy or minimize side effects

Acceptable dissolution limits to ensure bioequivalence

Risk assessment (Test to Reference exposure ratio for

bioequivalence or justification for new specifications)

Biowaivers (Avoid bioequivalence testing whenever

possible to allow filing of new products LCM + generics

without running human testing)



● IVIVe for BCS I modified release formulations

● Works well for short release (0-4h) in fasted state including hydrophilic

matrixes (Paracetamol, Zolpidem)

● Cardizem MR pellets (0-24H) works well in fasted state

● Darifenacin hydrophilic matrixes (5-20h) in fed state : IVIVc obtained using

deconvoluted absorption profile (multiple peaks) IVIVe not possible

(modeling of multiple peaks)

● IVIVe for BCS II modified release

● Worked for Felodipine in fasted state if vitro ensures “sufficient” sink

● Felodipine (5-20h) correlation in vivo abs more rapid than in vitro

dissolution ?

Need more examples of IVIVc/IVIVe to draw conclusions

One of the objectives of OrBiTo project (extend biowaivers)

http://www.orbitoproject.eu/



● Perspective for improvements of IVIVe

● More physiological PBPK models

• Transit patterns (partial gastric emptying, different transit rates with

impact of excipients and drugs)

• Mechanical forces (random + relation to food and nyctemeral cycle)

• Viscosity and diffusion in the lumen

• Free vs bound water (UWL)

● Link between in vitro performance and in vivo performance

• Dissolution methodology

• Viscosity, hydrodynamics, mechanical forces

• Selection of excipients for media (cf. Felodipine and Cardizem)

• Integration of dissolution/disintegration data in PBPK models

Allow a better estimation of within and between subject variability

Improve the in vitro-in vivo correlations


Acknowledgements

● Céline Ollier

● Amandine Mathieu

● Jun Chen

● Vanaja Kanamaluru

● Sylvie Fabre-Decourt

● Valérie Faillat Proux

● Véronique Hubert

● Catherine Marianne-dit-cassou

● Inga Gwose

● Catherine Janus

● Evelyne Chassagneux

● Nadine Quetand

● Anne Lanotte

● Çiğdem Bayka

● Shirishbhai Patel

● Yashwant Phadke

● Philippe Longuemard

● Dominique Beau

● Yuko Harada

● Olivier Rougeot

● Hervé Maze

● Jack Thomas

● Stéphane Beilles

● Louis Henrion

● Mathieu Faliph

● Jean-Pierre Collaveri

● Philippe Longuemard

● Victor Ariel

● Amithkumar Devgan

● Kum Prasad

● Priscilla Brun


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