Targeted Drug Delivery to the Lung

University of SheffieldEC funded COPHIT project

CFX Ansys......Areco.....................Aventis....…………….INO Therapeutics....University of Mainz..

UKFranceUKAustriaGermany

Partners

Outline

What is targetted delivery? – – the COPHIT project

Systemic model for whole respiratory system

Validation– Inhaled Nitric Oxide– Inhaled hyper-polarised 3He– Particles inhaled via dry powder inhaler

Inhaled drug delivery - I

Obvious: lung diseases – Asthma– COPD– Cystic Fibrosis– Pulmonary Hypertension

Inhaled drug delivery - II

New not-so-obvious therapies: – Diabetes - Insulin– Pain Management - Morphine– Multiple Sclerosis - Interferon Beta 1a– Osteoporosis - Parathyroid hormone– Infectious Disease - Antibiotics

Lots of advantages but ...

The metered dose inhaler

The drug is dissolved in the propellent

The actuation causes the drug to leave the device at 25 ms-1

Sub-optimal delivery ...

…sub-optimal results

Most of the drug impacts in the mouth

The small amount in the lungs is distributed only in the proximal airways

Controlled Entrainment

Targeted Drug DeliveryTargeted Drug Delivery

Controlled entrainment: Droplet/particle size Delivery timing Delivery duration …profiled to match the patient’s

characteristics

And is leading to a new generation of devices

Processor-controlled Adaptive

Multi-variant Optimisation

Hundreds of variables… Device characteristics Drug formulations Breathing patterns …

How to optimise? Only by modelling…

Ideal Model

Tell the model about… Device behaviour Drug characteristics Patient’s geometry, pathology, breathing

It reports back on… Deposition Uptake Effectiveness

COPHIT:

Project AIM

To develop a comprehensive dynamic compartmental model that can track the

progress of inhaled drug delivered from the device through the respiratory system and into

the circulation….

…validated in man by MR-imaging with hyper-polarised 3-He, and other techniques

Computer-Optimised Pulmonary Deliveryin Humans of Inhaled Therapies

Complex Physiological System The airways -

branching into several thousand pathways through more than 20 bifurcations

The lung - 300 million alveoli where drugs can be taken up across the alveolar membrane

3D Device from CAD

Model Compartments

3D airways to G8 from scans

0/1D compartments thereafter

Variable pathologies

G8: 28=256

3D URT geometry from scans

3D geometries from

medical images

Fill in missing detail

Segmentation ofhigh resolution CT scans

Geometry reassembled

Automatic surface mesh created

Upper Respiratory Tract

Tracheo-bronchial tree…

…down to the 8th generation

1.34 million volume elements (tets)Time ~4mins on a 800MHz P3 requiring ~1Gb Ram WP3

Diseased airways

Flow and Deposition Analysis Full Navier-Stokes equations solved in

3D geometry Subject to certain boundary conditions

Commercially-available CFD software package from partner– CFX 5.6 from CFX Ansys – Extra facilities for aerosol modelling

Transient flow: peak Re = 1200

t

V

Transient flow: peak Re = 1200

t

V

Transient flow: peak Re = 1200

t

V

Massless particles in transient flow

t=0.2-0.4s

Upper respiratory tract: transient

t=0.8-1s

WP3

Upper respiratory tract: transient

Validation

Validation – 5 Strategies 5 approaches to validation…

– Gas – Sampled (INO Therapeutics)

– Gas – MR Imaged (Mainz & Sheffield)

– Aerosols, Medical – Imaged (Aventis)

– Aerosols, Industrial – Analysed (Areco)

– Powders – Scintigraphically Imaged (Aventis)

Particles – Scintigraphy images 3 different inhaled regimens (A,B and

C) Scintigraphy images of inhaled

radiolabelled dry powder and aerosol Deposition calculated (from images)

as % of initial dose in – lung – oropharynx – oesophagus and stomach– exhalation filter– device

Particles – PK measurements Blood plasma concentration

measured.

Cromoglycate Plasma Concentration ECLIPSE OPTIMAL INHALATION

0.00

20.00

40.00

60.00

80.00

0 0.25 0.5 1 2 3 4 6

Time (hours)

ng/ml

Mean

Subject 1

Subject 2

Subject 3

Subject 4

Subject 5

Subject 6

Subject 7

Subject 8

-Scintigraphy - Results

– Regimen A: Eclipse™ at optimal inspiratory flow rate 50 L min-1

Eclipse™ optimal flow rate – 30% retention

24% initial dose26% initial dose

-Scintigraphy - Results

– Regimen B: Eclipse™ at sub-optimal inspiratory flow rate 30 L

min-1

Eclipse™ sub-Optimal flow rate – 50% retention

12% initial dose26% initial dose

-Scintigraphy - Results

– Regimen C: pMDI at optimal inspiratory flow rate 40 L min-1

pMDI Optimal flow rate – 9% retention

4% initial dose7% initial dose

Particles Simulations – Device

Particles Simulations – Mouth

0.5 m

3 m

7 m

20 m

50 m

Particles Simulations – Mouth

0.5 m

3 m

7 m

20 m

50 m

Particles3

Particles3

Dynamic deposition

Quantification of deposition data - I

Quantification of deposition data - II

Quantification of deposition data - III

44%

28%

3%

Gas Sampled

Artificially ventilated patients

Experimental trials at INO Therapeutics

Resulting mass fractions of NO - IIICoupled

Resulting mass fractions of NO - IIICoupled

Resulting mass fractions of NO - IVCoupled

Comparison with trial results – I Five points of measurement are identified

Trachea

Right main bronchus

Left main bronchus

Right down lobe

Left down lobe

Comparison with trial results – II

0.000

0.200

0.400

0.600

0.800

1.000

1.200

1.400

1.600

1.800

0.000 0.500 1.000 1.500 2.000 2.500 3.000 3.500 4.000

time / sec.

NO conc. / ppm

meas.

sim

Gas – MR imaged

Experimental trials at Sheffield

Gas – MR imaged

maximum temporal resolution =5.4 ms 1L of 3He and Nitrogen breathed

spontaneously from a bag gas composition = 300cm3 3He, 700cm3 N2

Experimental trials at Sheffield

Simulation results

Comparison with dynamic MRI - I

Comparison with dynamic MRI - II

Comparison with dynamic MRI - III

Software - processes

CFX

3-D fluids &

deposition solver

Coupled1-D

peripherysolver

Device

3DAirways

Solutioncalculation

choices

Solutionmodel

choices

Drug

DEFinition file…Initiatesolution

I N P U T S

Post-Processing and VisualisationCFXpostCFXpost

Flowpatterns

Drugdeposition

Simulink

O U T P U T S

Periphery

COPHIT workflow:

F l u i d s s o l v e r

Plasmalevels

…solved…

Easier to use front-end…

Uses web driven software – EASA from AEA Technology

All licensed software (e.g CFX etc) sits on a remote EASA server

Application driven from client’s computer by web browser and EASA client software

Conclusions

Comprehensive simulation tool developed

Allow pharma companies to test devices virtually before human trial

Enable clinicians to investigate specific pathological scenarios

Limitations:– Validation– Models