Targeted Drug Delivery to the Lung University of Sheffield EC funded COPHIT project CFX Ansys Areco Aventis....……………. INO Therapeutics.... University of Mainz.. UK France UK Austria Germany Partners

Outline  What is targetted delivery? –– the COPHIT project  Systemic model for whole respiratory system  Validation –Inhaled Nitric Oxide –Inhaled hyper-polarised 3 He –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 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 Delivery in Humans of Inhaled Therapies

Complex Physiological System The airways - branching into several thousand pathways through more than 20 bifurcations  The lung 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: 2 8 =256  3D URT geometry from scans

3D geometries from medical images Fill in missing detail Segmentation of high 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

t V

t V

Massless particles in transient flow

t= s 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.

 -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 dose 26% initial dose

 -Scintigraphy - Results –Regimen C: pMDI at optimal inspiratory flow rate 40 L min -1 pMDI Optimal flow rate – 9% retention 4% initial dose 7% initial dose

Particles Simulations – Device

Particles Simulations – Mouth 0.5  m 3 m3 m 7 m7 m 20  m 50  m

Particles Simulations – Mouth 0.5  m 3 m3 m 7 m7 m 20  m 50  m

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 - III Coupled

Resulting mass fractions of NO - III Coupled

Resulting mass fractions of NO - IV Coupled

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

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 = 300cm 3 3 He, 700cm 3 N 2 Experimental trials at Sheffield

Simulation results

Comparison with dynamic MRI - I

Comparison with dynamic MRI - II

Comparison with dynamic MRI - III

Software - processes

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