dissolution coupled with oral absorption modeling to predict
TRANSCRIPT
Dissolution coupled with oral absorption modeling to predict clinically relevant performance David Sperry, Nikolay Zaborenko and Kaoutar Abbou Oucherif Eli Lilly Third FDA/PQRI Conference on Advancing Product Quality March 22-24, 2017
Ā© 2017 Eli Lilly and Company
Outline
Biorelevant tools useful for drug development
Integrating in vitro and in silico models to predict in vivo performance
Three case studies
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Approach to biorelevant methods
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In Vitro Apps ā¢ Biorelevant fluids ā¢ Phenomenological
measurements
Models ā¢ Mechanistic
description
Mechanisms ā¢ Parameterize
models ā¢ Help translate in
vitro ā in vivo
Biorelevant product performance predictions
Best predictions
In Vivo Absorption Model
Biorelevant tools ā¢ In vitro apparatuses
ā USP-type paddle methods ā One-step and two-step ā Artificial Stomach Duodenum (ASD) model ā Scaled-down two-step dissolution ā Microcentrifuge test Biorelevant fluids ā SGF (FaSSGF, FeSSGF) ā FaSSIF, FeSSIF ā Simulated saliva
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See, for example: E. Jantratid and J. Dressman, āBiorelevant Dissolution Media Simulating the Proximal Human Gastrointestinal Tract: An Update,ā Diss. Tech., (2009) 16(3), 21.
Two-Step Dissolution ā¢ 300 mL 0.01 N HCl ā¢ 75 rpm paddle
ā 20 min ā¢ 300 mL FaSSIF ā¢ 75 rpm paddle
ā 260 min
USP-type methods: Example
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One-Step Dissolution ā¢ 900 mL FaSSIF ā¢ 75 rpm paddle
ASD model
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Stomach Secretion Rate = 2 mL/min
Duodenum Secretion Rate = 2 mL/min
Resting Volume = 50 mL Dosing Volume = 200 mL
Stomach Emptying: First order decay (w.r.t. Volume) Emptying Half-life = 15 min
Duodenum: Constant volume = 30 mL
Stomach
Duodenum
ASD measurements
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Stomach
Duodenum
Spec.
Light
Spec.
Light
Drug Dissolution Dilution and Transfer Out
Duodenum Data ā Key Output Upper intestinal drug concentrations can be used as a surrogate for drug Absorption.
Stomach Data ā Context Additional information can be learned from stomach profiles.
Biorelevant tools
ā¢ Mechanisms ā Rotating disk dissolution (RDD, intrinsic
dissolution) ā Flow-through imaging ā NMR ā Focused beam reflectance measurement
(FBRM)
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Diffusion coefficient
ā¢ Intrinsic dissolution rate: Solve Navier-Stokes for a rotating disk (Levich equation)
ā¢ Stokes-Einstein: laminar viscous drag on a spherical molecule
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Diffusion coefficient by other methods
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ā¦ Flow-through UV Imaging (SDi300)
http://www.sirius-analytical.com/system/files/Sirius%20Application%20 Note%20304-13%20UK%20web.pdf
ā¦ Diffusion-Ordered Spectroscopy 2D NMR
LasentecĀ® FBRMĀ® experiments
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half way btw wall and shaft
Front view Side view
~20o angle
~ 1 cm from top of paddle
High pH
Low pH
Intermediate pH
Slide courtesy of Carrie Coutant
Biorelevant tools
ā¢ Dissolution Models
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Granules Tablet Powder Disintegration Disintegration
Very Limited Dissolution
Limited Dissolution
Best Dissolution
Limited physical models -> simple 1st-order rate
Limited physical models -> simple 1st-order rate
Good physical models
Hydrodynamics
Dissolution model ā¢ Noyes-Whitney dissolution model,
with several enhancements.
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0 10 20 300
0.5
1
t
Dissolved Coated tablet
Tablet
Granules
Aggregates
API
32134 rrrV Ļ=
šš1,2,3
ššļæ½min š1,2,3 >0
= āšš”š”š”š”š”š”
šššššļ潚š>0
= āšššš”š
Tablet and granule disintegration
Henderson-Hasselbalch, pH and buffer capacity
APIāAPI+
HPO42-
H2PO4-
PO43- pH
Sol
parti
cle
Surface concentration
0.1 1 10 1000
0.05
0.1Particle size distribution
mi
r0i
Population balance
In vitro-in silico approach
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Biorelevant product performance predictions In Vitro Apps
Models Mechanisms
In Vivo Absorption Model
Johnson model
Input CR profile z-factor Fitted PSD Fitted D Mechanistic
parameters
Case 1 ā Modified release formulation ā¢ Overall development challenge
ā Increase the throughput of the process by a simple formulation change: increase the drug-containing layer thickness thereby increasing the drug load.
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ā¢ Formulation A ā Spray-coated bead ā Bead enteric coated
ā¢ āNewā high-drug load formulation B ā Drug load increased ~50% by spray-
coating more drug on bead ā Other aspects remain the same
Core
Drug layer
Enteric coat * Some details of formulation omitted for clarity
Sperry et al., Molecular Pharmaceutics, 2010, 7, 1450ā1457.
In vitro dissolution ā¢ Different strengths tested in vitro by different
methods
ā¢ Many method conditions explored ā e.g. Both paddles and baskets specifically
investigated.
ā¢ Dissolution is different between formulations ā¢ And difference is not an artifact of the test
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A
B
Sperry et al., Molecular Pharmaceutics, 2010, 7, 1450ā1457.
In vitro modeling
ā¢ Agreement suggests differences in release rate observed in vitro are due purely to the difference in surface area.
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Sperry et al., Molecular Pharmaceutics, 2010, 7, 1450ā1457.
( ) ( )
āā
+āā ā
āā ā ā ā ā
=VXCrrr
XX
rrhXD
dtdX d
sccs
c
s3
2
3330
033
0
03Ļ
0.1 1 10 1000
0.05
0.1Particle size distribution
Mas
s in
bin
mi
r0i
rc
r0
Bioequivalence study ā¢ Met bioequivalence criteria
of 0.8 and 1.25
In this case, simple buffers and USP II method produced adequate biorelevant predictions.
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Sperry et al., Molecular Pharmaceutics, 2010, 7, 1450ā1457.
Case 2 ā Free base conversion ā¢ Solid forms: free base & a salt ā¢ Properties: Low solubility, pka ~7
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FaSSIF Salt Dissolution
Conversion to free base
Rotating Disk Dissolution
Free base
Salt
ASD: Salt supersaturation and precipitation
Stomach concentrations Duodenum concentrations
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Low dose
High dose D0=450
D0=120
D0=0.1
D0=0.03
Distribution of gastric conditions
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Normal
With PPI population
Map of Gastric conditions
In Vivo Absorption Model
Dissolution input
Systems-based Pharmaceutics
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- Linking manufacturing excellence with patient performance
Alliance
Case 3 ā Integrating ASD data ā¢ Low solubility base
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ASD Duodenum Concentration
In Vivo Absorption
Model
In vitro ASD
In silico ASD
Dissolution/precipitation parameters
Precipitation rate parameters
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Model parameter Final value Initial guess 95% C.I Standard deviation
Growth constant 0.55 0.36 1.42 0.70 Growth order 1.60 0.81 2.29 1.13 Nucleation coefficient 14.01 13.85 974.9 481.2 Nucleation order 2.61 2.77 399.3 197.1
Ā© 2017 Eli Lilly and Company
Duodenal Concentration Profile
Incorporating ASD results in gCOAS GI model
ā¢ 15 mg dose ā Precipitation is predicted to be negligble. Fa =1
ā¢ 50 mg dose ā Fa =0.82 due to precipitation in the
small intestine 22 March 2017 25
50 mg dose
15 mg dose
Ā© 2017 Eli Lilly and Company
Acknowledgements
ā¢ Lee Burns ā¢ Carrie Coutant ā¢ Todd Gillespie ā¢ Brian Winger
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