An in vivo predictive dissolution methodology (iPD methodology) can

predict the in vivo bioequivalence results: Etoricoxib and

Dexketoprofen products

Marival Bermejo
Professor
Pharmacy and Pharmaceutical Technology
School of Pharmacy
Universidad Miguel Hernández, Elche, Spain
mbermejo@umh.es
BIOEQUIVALENCE

Drug Formulation
Formulation A Formulation B

Dissol in Vivo Dissol in Vivo

Drug substance
Absorption Absorption
Intestinal Membrane
Distribution Distribution
Metabolism Metabolism
Excretion Excretion
 Class I:HS/HP Class II:LS/HP

Verapamil, Proparanolol Carbamazepine,

Metoprolol Ketoprofen, Naproxen
Permeability

Class III:HS/LP Class IV: LS/LP

Ranitidine, Cimetidine, Furosemide,

Atenolol Hydrochlorothiazide

Volume of aqueous buffer to dissolve the highest dose

 Dissolution tests: QC vs IPD
• Quality control:
• Process control Keep It Short and Simple • Pharmacopoeial apparatus,
• Batch-to-batch quality • single media,
• few samples

• Predictor of Product performance In vivo

BCS
Experimental aspects:
Apparatus, biorelevant media
In vivo predictive dissolution

Ensuring dissolution is NOT Mathematical aspects:

Mimicking in vivo dissolution: One step, versus Two steps
the limiting step:
Average vs individual
IVIVC-based biowaivers Specification setting
BCS-based Biowaivers for
class 1 and 3
What is an IVIVC?: Definition
• A predictive mathematical model describing the
relationship between an in vitro property of the
formulation (i.e dissolution rate) and the in vivo
response (i.e absorption profile or plasma levels).

IVIVC goal

 To use the dissolution test as a surrogate BE trial:

Biowaiver based IVIVC.
 Use the IVIVC as a development tool for
formulation selection.
IVIVC approaches: two steps
plasma levels
10.00 Dissolution test
100
90
80
conc mg/mL

70

Dissolved fraction
1.00 60
50
40
30
20
10
0.10 0
0 200 400 0 100 200 300 400 500
time (min)
tim e (min)

Wagner Nelson Plot

120

100
Absorbed/bioavailable fraction

80

60

40

20

0
0 100 200 300 400 500
tim e (min)
IVIVC approaches: one step
Dissolution test plasma levels
10.00
100
90
80
70
Dissolved fraction

conc mg/mL
60
50 1.00
40
30
20
10
0
0 100 200 300 400 500 0.10
tim e (min) 0 200 400
time (min)

Link Model
IVIVC approaches: two steps
plasma levels
10.00 Dissolution test
100
90
80
This is not an IVIVC
conc mg/mL

70

Dissolved fraction
1.00 60
50
40
30 IVIVC
20
10 120
0.10 0 100
0 200 400 0 100 200 300 400 500
time (min) 80
tim e (min)

Fabs
60
40
20
0
0.00 50.00 100.00 150.00
Wagner Nelson Plot
Fdiss
120

100
Absorbed/bioavailable fraction

80

60 Is there a relationship between

40 dissolution and Plasma levels?
20

0
0 100 200 300 400 500
tim e (min)
In vivo predictive dissolution IPD
GOAL: Integrate, physical
chemistry and physiology
Gastric emptying Intestinal transit

Absorption
and relate in vitro results
Dissolution
to in vivo performance

with in vivo relevant dissolution

methodologies

The “human to predict what happens

beaker” in the in vivo
environment

Source Prof. Greg Amidon

Gastrointestinal simulator V.1
examples of BE failed studies that can
be predicted by GIS device

• Desketoprofen trometamol (weak acid salt Class 1)

• Etoricoxib (Class 2 weak base)
http://www.ddfint.org/gastro-intestinal-simulator/
https://youtu.be/a6VZDMX6kC4
Gastrointestinal simulator
GIS version 0.0
http://www.ddfint.org/gastro-intestinal-simulator/
https://youtu.be/a6VZDMX6kC4
Dexketoprofen Trometamol
Salt of a weak acid
Class 1 BCS. Log P 3.12; MW 375.42 g/mol F>85%
 Confidence Interval 90%
Failed BE BE

Cmáx 102.65 – 132.10 % 90.46 – 108.51%

AUC-∞ 98.78 – 104.02% 104.29 – 111.82%

stomach duodenum jejunum
Figure 8. Diagram showing the DKT transformations to DK drug phases during dissolution. A more soluble
drug phase appears first as liquid–liquid phase separation (LLPS), followed by a less soluble crystalline
phase. The kinetics and pathways of these transformations are dependent on salt concentration,
formulation excipients and level of drug phase impurity in the salt phase.

Excipients that increase pH (calcium phosphate) decreased free acid precipitation

and enhanced dissolved levels of drug in the non-BE formulation. The BE product
was associated with a faster conversion to KT crystals, whereas non-BE product
experienced less drug precipitation under the same condition.
IN VIVO fa Loo-riegelman
DKT IVIVC with GIS dissolution results in jejunum

Cmax AUC
Cmax pred AUC exp pred
exp ng/L ng/L ER% ng/L*h ng/L*h ER%
Reference 2430.6 2576.3 -5.99 2497.3 2520.2 -0.92
No BE 3177.3 3062.5 3.61 2785.7 2738.6 1.69
BE 2478.5 2491.9 -0.54 2626 2538.1 3.35
Average 3.38 1.98
Etoricoxib Class 2 FQ INFORMATION

Molecular weight=358.85

Log D=2.28 (pH 7.0)

pKa=4.5 WEAK BASE

BCS HS LS
ETORICOXIB

Class I Class II
HP
Caco-2 permeability=5.23×10−5 cm/s HS/HP LS/HP

Calculated human permeability

(from Caco-2 data)=4.75×10−4 cm/s
Class III Class IV
LP
Reference contains Calcium phosphate
HS/LP LS/LP
 Confidence Interval 90%
NoBE BE
Cmáx 111.26– 125.57 % 104.27 – 121.54%
AUC-∞ 97.54 – 103.50% 99.10 – 106.97%

Reference contains Calcium Phosphate.

BE product reduced crosscarmellose content vs NonBE

 Stomach: 50 mL HCL 0.01 N+ 34.2 mM NaCL + 250 mL

water
 Gastric secretion: HCL 0.01 N+ 34.2 mM NaCL
 Duodenum: Phosphate Buffer 5mM pH 6.5
 Duodenal secretion Phosphate Buffer 100 mM pH 6.5
 Amounts in GIS chambers

Failed BE BE Reference
stomach

duodenum

jejunum
Mass transport analysis GIS: Amounts/Volume= conc.
Secretions
1ml/min

Stomach Duod Jejunum

Volume changes
Mass transport analysis GIS
Mass transfer
Stomach solid

Stomach
dissolved
Duodenum solid

Jejunum solid
Mass transport analysis GIS
Precipitation

Dissolution
Mass transport analysis Intestine
Mass transit

Permeation

Absorption/availability
 Dissolution f(pH) 10 −𝑝𝑝𝑝𝑝_𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠
Cs segment = 𝐶𝐶𝑠𝑠 0 � 1+ Volumes
10 −𝑝𝑝𝑝𝑝𝑝𝑝

Solid dissolution

Transit GIS Transit Vivo to colon

Absorption
Plasma

Precipitation

Model based on Matsui K. et al PMID: 28231003

Etoricoxib Class 2 Weak base. stomach
In vivo predictions from in vitro GIS results
(Model based in Matsui et al. Mol Reference
pharmaceutics 2017): PMID: 28231003
Kpre_J Z_d
cv% cv%
(min-1) (mL/mg/min)
Test NoBE 3.18E-02 63.1 3.51E-05 13.5
Test BE 8.30E-02 36.3 3.10E-05 6.6 duodenum
Reference 7.84E-02 79.3 1.45E-05 9.1

Cmax ratio Predicted Experimental BE

Test BE 1.18 1.12
Test No BE 1.27 1.18
Dissolution/precipitation
parameter ratio
1.10 Failed BE jejunum
Failed BE
0.37 BE
0.18 Reference
Conclusions
• GIS apparatus is a useful developmental tool for IR oral formulation
development (physiologically-relevant media and conditions)
• Relevant GI variables for the development of ‘In Vivo Product Predictive
Dissolution Methods’ need to be adapted to each compound.
• Selection of dissolution conditions for the GIS device depend on
• (i) the BCS profile of the drug and ionization characteristics.
• (ii) its formulation characteristics.
• The ionic strength, buffer strength and surfactants impact on the
supersaturation/precipitation balance needs to be further investigated .
Acknowledgments Questions and Contact Information

• Prof Gordon Amidon, P.I. UM Marival Bermejo Sanz

• Prof Gregory Amidon, P.I. UM
Universidad Miguel Hernández. Campus de
• Dr Bart Hens, U Leuven San Juan
• Assoc. Prof. M Isabel González-Alvarez. Edificio 2 Departamentos
UMH
Carretera Alicante-Valencia sn Km 87.
• Dr. Alfredo García Arieta AEMPS. 03550
Funding: FDA San Juan de Alicante
• HHSF223201510157C Spain
• HHSF223201310144C mail: mbermejo@umh.es
 Acknowledgements

Isabel González-Alvarez
Paulo Paixao
Hiro Tsume
Bart Hens
Gordon Amidon