| 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
| 2 Xavier Pepin – AAPS meeting 4th Nov 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)
| 3 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 4 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 5 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 6 Xavier Pepin – AAPS meeting 4th Nov 2014
Case study #1
Paracetamol “night” Define release rate and administration time
to achieve maximum pain relief during the
night for a 1 g tablet
| 7 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 8 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 9 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 10 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 11 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 12 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 13 Xavier Pepin – AAPS meeting 4th Nov 2014
Case study #2
Zolpidem ODT Define bioequivalent dissolution range for
immediate release Zolpidem products
| 14 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 15 Xavier Pepin – AAPS meeting 4th Nov 2014
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
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Verification on oral IR products
Good fit of IR profiles in
caucasians
Good fit of IR profiles in
japanese
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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
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Sensitivity analysis
● Stomach transit time
● Major reduction on Cmax and increase in tmax
● No anticipated effect on AUC
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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
| 20 Xavier Pepin – AAPS meeting 4th Nov 2014
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)
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
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)
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
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
| 21 Xavier Pepin – AAPS meeting 4th Nov 2014
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 ?
| 22 Xavier Pepin – AAPS meeting 4th Nov 2014
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]
| 23 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 24 Xavier Pepin – AAPS meeting 4th Nov 2014
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
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Diltiazem extended release IVIVe with pH 1 data
In vivo dissolution is ~6h quicker
than in vitro dissolution
| 26 Xavier Pepin – AAPS meeting 4th Nov 2014
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 !
| 27 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 28 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 29 Xavier Pepin – AAPS meeting 4th Nov 2014
Case study #4
Felodipine ER Development of a biowaiver in support of
site manufacturing change (Astra-Zeneca,
Sweden to Zentiva, Turkey)
| 30 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 31 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 32 Xavier Pepin – AAPS meeting 4th Nov 2014
Felodipine – GastroPlus model building
● Full PBPK model
● Human American male of 32y/o + 73 kg
| 33 Xavier Pepin – AAPS meeting 4th Nov 2014
Felodipine – GastroPlus model building
● 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
| 34 Xavier Pepin – AAPS meeting 4th Nov 2014
Felodipine – GastroPlus model building
● 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)
| 35 Xavier Pepin – AAPS meeting 4th Nov 2014
Goodness of fit – oral solutions
● Model considered adequate for IR products
Acceptable anticipation of
Cmax and AUC
| 36 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 37 Xavier Pepin – AAPS meeting 4th Nov 2014
Felodipine tablet A Direct IVIVe
● Use of the Weibull 2 phase function to fit in vitro data
● In vitro in vivo
| 38 Xavier Pepin – AAPS meeting 4th Nov 2014
Felodipine tablet B Direct IVIVe
● Use of the Weibull 2 phase function to fit in vitro data
● In vitro in vivo
| 39 Xavier Pepin – AAPS meeting 4th Nov 2014
Felodipine tablet C Direct IVIVe
● Use of the Weibull 2 phase function to fit in vitro data
● In vitro in vivo
Almost complete metabolism
of fraction absorbed upper GI
| 40 Xavier Pepin – AAPS meeting 4th Nov 2014
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 ?
| 41 Xavier Pepin – AAPS meeting 4th Nov 2014
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 ?
| 42 Xavier Pepin – AAPS meeting 4th Nov 2014
Felodipine tablet C Use of PK profile to fit in “vivo dissolution”
● In vivo in vitro In vivo release more complete than in vitro ?
| 43 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 44 Xavier Pepin – AAPS meeting 4th Nov 2014
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)
| 45 Xavier Pepin – AAPS meeting 4th Nov 2014
Case study #5
Darifenacin 15 mg ER Generic formulation development
Impact of physiology on model construction
| 46 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 47 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 48 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 49 Xavier Pepin – AAPS meeting 4th Nov 2014
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%
| 50 Xavier Pepin – AAPS meeting 4th Nov 2014
Direct IVIVe with Darifenacin pH 6.8 data
● Use of the Weibull single phase function as input
Overestimation of
PK from 10 hours
| 51 Xavier Pepin – AAPS meeting 4th Nov 2014
Direct IVIVe with Darifenacin pH 6.8 data
● Dissolution of the tablet in the lower segments of the GI tract
Majority of the drug
absorbed from the
lower segments
| 52 Xavier Pepin – AAPS meeting 4th Nov 2014
Direct IVIVe with Darifenacin pH 6.8 data
● 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
| 53 Xavier Pepin – AAPS meeting 4th Nov 2014
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 ?
| 54 Xavier Pepin – AAPS meeting 4th Nov 2014
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 ?
| 55 Xavier Pepin – AAPS meeting 4th Nov 2014
Cp time profiles for individual subjects
● Peaks and troughs in the PK profiles
| 56 Xavier Pepin – AAPS meeting 4th Nov 2014
Cp time profiles for individual subjects
● Peaks and troughs in the PK profiles
| 57 Xavier Pepin – AAPS meeting 4th Nov 2014
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)
| 58 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 59 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 60 Xavier Pepin – AAPS meeting 4th Nov 2014
Analysis of individual profiles for 20 subjects
● 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
| 61 Xavier Pepin – AAPS meeting 4th Nov 2014
Analysis of individual profiles for 20 subjects
● 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
| 62 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 63 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 64 Xavier Pepin – AAPS meeting 4th Nov 2014
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)
| 65 Xavier Pepin – AAPS meeting 4th Nov 2014
Conclusions - Perspectives
● 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/
| 66 Xavier Pepin – AAPS meeting 4th Nov 2014
Conclusions - Perspectives
● 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
| 67 Xavier Pepin – AAPS meeting 4th Nov 2014
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
| 68 Xavier Pepin – AAPS meeting 4th Nov 2014
Back up slides