The fate of inhaled drugsThe fate of inhaled drugs

Mark EverardSheffield Children’s Hospital

Why Used Inhaled Therapy?

Drug is delivered directly to site of actionSpahan JD, Szefler SJ Pediatric Respiratory Medicine 2008

Oral vs Inhaled therapy Fundamental differences

Lungs have evolved to exclude foreign material

Even if you take the medication you may not Even if you take the medication you may not derive any benefitderive any benefit

Compliance x 2Compliance x 2regimen compliancedevice compliance

[competence + contrivance]

Inhaled Therapy for Pulmonary DiseaseInhaled Therapy for Pulmonary Disease

Speed of Onset

Therapeutic Index

Large luminal dose

Poorly absorbed drugs

Webb J et al Br J Dis Chest 1982

Inhaled Therapy for Systemic TherapyInhaled Therapy for Systemic Therapy

Very Large surface area

Therapeutic effectDrug

Inhaled TherapyDevice / Formulation

Therapeutic effectDrug

Inhaled Therapy -ISAM

Device

Formulation issuesAvailability

CostTarget

AnatomyPhysiology

Disease

Inter- subject

variation

Age dependent

Adverse Effects

Generalised

Variable

Progressive

Fate of drug

Therapeutic effect

Drug

Sources of Variability in Lung Dose

Device

Formulation issuesAvailability

CostTarget

AnatomyPhysiology

Disease

FixedProgressive

Variable

Inter- subject

variation

Age dependent

How controlled?

Adverse Effects

Compliance

Competence

Contrivance

DepositionDepositionImpaction Impaction SedimentationSedimentationBrownian motion

DefencesDefences

Airways anatomyAirways anatomy

CoughMucocillary clearance

Basic PrinciplesBasic PrinciplesLungs have evolved to exclude foreign material

Energy Is Required for Energy Is Required for AerosolisationAerosolisation

Jet nebuliser compressed aircompressed air

pMDI CFC / HFA

Dry powder patient

Lung Dose Variability Lung Dose Variability --

Healthy AdultsHealthy Adults

IntraIntra--subject subject CV%CV%

Urinary Salbutamol (μg)

‘Most efficient’

pMDIpMDI 50.1 %[27-146.8]

5.4[0.69-17.6]

pMDI+HCpMDI+HC 31.7 %[20.1-87]

11.6[2.2-35.9]

77

Breath ActuatedBreath Actuated 33.4 % [10.5-61.9]

8.8[2.2-13.2]

22

AccuhalerAccuhaler//DiscusDiscus

39.6 %[12.4-75.2]

9.6[4.1-14.7]

33

TurbohalerTurbohaler 42.4 %[21.0-73.8]

7.5[2.6-17.6]

11

Everard et al J Aerosols Med

450 Mill. Alveoli Surface Area of 150 m2

Diameter ¼ mmGasex-change Area 80-90%

‘Bacterial Chest Infections’

Drug Delivery is NonDrug Delivery is Non--UniformUniform

0

0.05

0.1

0.15

0.2

0.25

0 5 10 15 20 25

Generation number

Depo

sitio

n pe

r uni

ts s

urfa

ce

area

(%/s

q cm

)

0

0.2

0.4

0.6

0.8

1

1.2

1.4

0 5 10 15 20 25

Generation number

Depo

sitio

n pe

r un

it vo

lum

e (%

/ml)

05

10152025303540

0 5 10 15 20 25

Generation number

Dep

ositi

on p

er g

ener

atio

n

John Fleming, Southampton Martonen 2003

Distribution of Aerosol Deposition

Does Breathing Pattern Matter?

Impact of DiseaseImpact of Disease

-

Asthma

Martonen 2003

Laube B 1992

Impact of DiseaseImpact of Disease

-

Asthma

Impact of DiseaseImpact of Disease

Fate of Deposited Particles

Mucocillary

Clearance & Absorption

Becker RHA 2006

Borgstrom 1992

Reddel H Lancet 1999

Poor control vs

Exacerbation

Biofilms

Bacterial Bronchitis inc CF, bronchiectasis, COPD

COPD and Insulin

Therapeutic effectDrug

Inhaled Therapy

Device

Formulation issuesAvailability

CostTarget

AnatomyPhysiology

Disease

Inter- subject

variation

Age dependent

Adverse Effects

Generalised

Variable

Progressive

Fate of drug

SummaryWe are taking on the forces of evolution, pathogens and disease [& regulators!]

Aerosol are best used in healthy individuals

Intervene early while you can effectively

Asthma is relatively easy