Dissolution coupled with oral absorption modeling to predict

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

© 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 • Biorelevant fluids • Phenomenological

measurements

Models • Mechanistic

description

Mechanisms • Parameterize

models • Help translate in

vitro → in vivo

Biorelevant product performance predictions

Best predictions

In Vivo Absorption Model

Biorelevant tools • In vitro apparatuses

– USP-type paddle methods – One-step and two-step – Artificial Stomach Duodenum (ASD) model – Scaled-down two-step dissolution – Microcentrifuge test Biorelevant fluids – SGF (FaSSGF, FeSSGF) – FaSSIF, FeSSIF – Simulated saliva

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See, for example: E. Jantratid and J. Dressman, “Biorelevant Dissolution Media Simulating the Proximal Human Gastrointestinal Tract: An Update,” Diss. Tech., (2009) 16(3), 21.

Two-Step Dissolution • 300 mL 0.01 N HCl • 75 rpm paddle

→ 20 min • 300 mL FaSSIF • 75 rpm paddle

→ 260 min

USP-type methods: Example

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One-Step Dissolution • 900 mL FaSSIF • 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 – Key Output Upper intestinal drug concentrations can be used as a surrogate for drug Absorption.

Stomach Data – Context Additional information can be learned from stomach profiles.

Biorelevant tools

• Mechanisms – Rotating disk dissolution (RDD, intrinsic

dissolution) – Flow-through imaging – NMR – Focused beam reflectance measurement

(FBRM)

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Diffusion coefficient

• Intrinsic dissolution rate: Solve Navier-Stokes for a rotating disk (Levich equation)

• Stokes-Einstein: laminar viscous drag on a spherical molecule

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Diffusion coefficient by other methods

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♦ Flow-through UV Imaging (SDi300)

http://www.sirius-analytical.com/system/files/Sirius%20Application%20 Note%20304-13%20UK%20web.pdf

♦ Diffusion-Ordered Spectroscopy 2D NMR

Lasentec® FBRM® 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

• 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 • 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 π=

𝜕𝑟1,2,3

𝜕𝜕�min 𝑟1,2,3 >0

= −𝑘𝑡𝑡𝑡𝑡𝑡𝑡

𝜕𝑟𝑖𝜕𝜕�𝑟𝑖>0

= −𝑘𝑔𝑟𝑡𝑔

Tablet and granule disintegration

Henderson-Hasselbalch, pH and buffer capacity

API↔API+

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 – Modified release formulation • Overall development challenge

– 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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• Formulation A – Spray-coated bead – Bead enteric coated

• “New” high-drug load formulation B – Drug load increased ~50% by spray-

coating more drug on bead – Other aspects remain the same

Core

Drug layer

Enteric coat * Some details of formulation omitted for clarity

Sperry et al., Molecular Pharmaceutics, 2010, 7, 1450–1457.

In vitro dissolution • Different strengths tested in vitro by different

methods

• Many method conditions explored – e.g. Both paddles and baskets specifically

investigated.

• Dissolution is different between formulations • And difference is not an artifact of the test

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A

B

Sperry et al., Molecular Pharmaceutics, 2010, 7, 1450–1457.

In vitro modeling

• 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, 1450–1457.

( ) ( )

−⋅

+−⋅⋅

−⋅⋅⋅⋅−

=VXCrrr

XX

rrhXD

dtdX d

sccs

c

s3

2

3330

033

0

03ρ

0.1 1 10 1000

0.05

0.1Particle size distribution

Mas

s in

bin

mi

r0i

rc

r0

Bioequivalence study • 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, 1450–1457.

Case 2 – Free base conversion • Solid forms: free base & a salt • 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 – Integrating ASD data • 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

© 2017 Eli Lilly and Company

Duodenal Concentration Profile

Incorporating ASD results in gCOAS GI model

• 15 mg dose – Precipitation is predicted to be negligble. Fa =1

• 50 mg dose – Fa =0.82 due to precipitation in the

small intestine 22 March 2017 25

50 mg dose

15 mg dose

© 2017 Eli Lilly and Company

Acknowledgements

• Lee Burns • Carrie Coutant • Todd Gillespie • Brian Winger

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