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TRANSCRIPT
The DDL Lecture 2016
THE CHALLENGE OF DELIVERING INHALED DRUGS TO THE LUNGS
Dr Stephen Newman
Scientific Consultant, Norfolk, UK
HISTORICAL BACKGROUND
Pulmonary drug delivery used for > 3000 years Inhalation of smoke from burning herbal preparations
19th century Inhaled creosote, chlorine, hemlock, etc……. (BP, 1867) Ceramic and metal vapour inhalers
First half of 20th century Inhaled adrenaline, insulin, antibiotics Lack of success owing to poor understanding of scientific, technical
and medical issues? Second half of 20th century / 21st century
Modern inhalers and modern drugs Much improved understanding Journals, conferences, educational courses, networking
Stein S and Thiel C, J Aerosol Med Pulm Drug Deliv 2016; 29: epub.
PULMONARY DRUG DELIVERY ROUTE:TOPICAL AND SYSTEMIC APPLICATIONS
Asthma / COPD maintenance therapy Bronchodilators – beta-adrenergic; anti-muscarinic – long-acting Inhaled corticosteroids (ICSs) Combination products, e.g. Advair® Diskus®
Other topically acting drugs: treatment of orphan diseases Antibiotics, mucolytics in cystic fibrosis (CF) Prostacyclin analogues in pulmonary arterial hypertension (PAH) Potential future therapies, e.g. treatment of lung transplant rejection,
idiopathic pulmonary fibrosis.
Systemically acting drugs for common medical conditions Fast acting small molecules, e.g. analgesics Peptides and proteins, e.g. insulin Vaccines, e.g. measles vaccine
ADVANTAGES OF PULMONARY ROUTE
Topically acting drugs Drug is targeted to its site of action Systemic absorption not required for efficacy Low dose compared to oral therapy Low incidence of systemic side-effects, e.g. corticosteroids Rapid onset of drug action, e.g. bronchodilators
Systemically acting drugs Drug is targeted to its site of absorption Avoids injection for drugs not absorbed from GI tract Pulmonary epithelium: > 100 m2 with thin epithelial barrier Rapid onset of drug action, e.g. analgesics More advantageous pharmacokinetics, e.g. mealtime insulin
FOUR BASIC DEVICE TYPES OF INHALER
Pressurized metered dose inhalers (pMDIs)
Dry powder inhalers (DPIs)
Nebulizers
Next generation portable technologies
Each inhaler type has its own advantages and disadvantages
Formulation and device equally important
INHALER SELECTION:MASS OF DRUG CONTAINED IN ONE DOSE
1 µg 10 µg 100 µg 1 mg 10 mg 100 mg
pMDI, multi-dose (reservoir) DPI
Unit-dose DPI, multiple unit-dose DPI
High-payload unit-dose DPI
Nebulizer
Asthma and COPD drugs Insulin Antibiotics
WHAT IS THE CHALLENGE ?
“The major challenge in the development of inhalable compounds is limited understanding of the relationship between pharmacokinetic (PK) and pharmacodynamic (PD) effects in the lung” (Cabal A et al, DDL-27)
Converting a promising prototype inhaler into a commercial success ?
Collecting clinical data to secure approval of your product ?
To ensure a predictable, reproducible lung dose and clinical effect with each treatment, while minimising side-effects, and to achieve this at reasonable cost
The patient presents the biggest barrier to meeting this challenge Natural lung defence mechanisms evolved to prevent entry of inhaled particles…. …..and to eliminate them once deposited The need to use an inhaler, and use it correctly
Pulmonary drug delivery is much more complex than taking a tablet
THE RESPIRATORY TRACT: BASIC ANATOMYUPPER AIRWAYS(Extrathoracic airways)
BRONCHIAL TREE(Weibel model:23 branching generations)
TRACHEA
CONDUCTING (TRACHEOBRONCHIAL) AIRWAYS
Bronchi
Bronchioles
Nasal passages
ALVEOLATED AIRWAYS
Mouth, pharynx and larynx
PATIENT BARRIERS TO SUCCESSFUL DRUG DELIVERY
Non-adherence to treatment regimen
Poor inhaler technique
Actions of enzymes,surfactant, etc.
Engulfment by alveolar macrophages
Impaction of particles and droplets in nose and mouth
Poor aerosol penetration to lung periphery
Lung mucociliaryclearance of drug
MECHANICALBARRIERS
CHEMICALBARRIERS
BEHAVIOURALBARRIERS
IMMUNOLOGICALBARRIERS
Effects of disease
From Heyder J et al, J Aerosol Sci 1986; 17: 811-825
Controlled breathing of monodisperse particles; Inhaled volume 1.5 L, Inhaled flow rate 45 L/min
DEPOSITION OF DIFFERENT PARTICLE SIZES FOR MOUTH BREATHING
From Heyder J et al, J Aerosol Sci 1986; 17: 811-825
Controlled breathing of monodisperse particles; Inhaled volume 1.5 L, Inhaled flow rate 45 L/min
DEPOSITION OF DIFFERENT PARTICLE SIZES FOR NOSE BREATHING
THE UPPER AIRWAYS: A VARIABLE APERTURE
Cross-sectional area, mm2
200
400
600
800
Mouth Oropharynx Larynx
DPI
pMDI
Mean and SD data from Ehtezazi T et al, J Aerosol Med; 2004: 17; 325-334
DEPOSITION IN THE RESPIRATORY TRACT: SUMMARY
Respiratory tract has evolved to keep inhaled particles out of the lungs
The nasal passages are a very effective aerosol filter
Aerodynamic particle diameter < 5 µm for whole lung delivery
Aerodynamic particle diameter < 3 µm for peripheral lung delivery
Inhaled flow rate, inhaled volume and carrier gas important
Most inhalers deposit less than 20 % of the dose in the lungs
Lung deposition is potentially highly variable
LUNG DEPOSITION FROM INHALER DEVICESFrom Borgström L et al, J Aerosol Med 2006; 19: 473-483
Coefficient of Variation
%
30
60
90
Mean lung deposition, % ex-valve20 40
Data from 71 deposition studies Poor inhaler technique will lead to additional variability
ASTHMA / COPD:(most products)Low-cost potent molecules ORPHAN DISEASES /
SYSTEMIC DELIVERY:Dosing precisionEfficient delivery to lungsCost-effectiveness
FATE OF INHALED DRUGSFigure adapted from Patton JS et al, J Aerosol Med Pulm Drug Deliv 2010; 23: S71-S87
Depositing drug particle
Dissolution
Mucociliaryclearance
Topical efficacy
Absorption
Enzymatic degradation
Engulfment by alveolar macrophages
Small molecules(e.g. loxapine, MW 328 Da; fentanyl, MW 336 Da) Rapid and efficient absorption, particularly
lipophilic compounds
Peptides(e.g. calcitonin, MW 3418 Da; insulin, MW 5786 Da) Absorption slower and less efficient Bioavailability highly compound-specific Enzymatic degradation potentially reduces
absorption
SMALL MOLECULES vs PEPTIDESFOR SYSTEMIC ACTION
STRATEGIES FOR ENHANCING DELIVERY OF INHALED DRUGS
Reducing chemical and immunological barriers PEGylation Absorption enhancers Novel particle strategies, e.g. Large porous particles
Active transport of large molecules (conducting airways)
Increasing retention / duration of action Controlled release
Bioadhesive formulations, e.g. PLGA microparticles
“Molecular engineering”, e.g. LABAs
Increasing efficiency of delivery system Device and / or formulation “Engineered particles”
AERx®, Aradigm
Large porous particles, Alkermes
THE CHALLENGE OF DELIVERING INHALED INSULIN
Requires efficient and reproducible pulmonary delivery Alveolar targeting Bioavailability limited: 2 in 3 deposited molecules usually not absorbed intact 1
Narrow therapeutic window Most developments have involved dry powder formulations
Stability; low susceptibility to bacterial growth
First inhaled insulin product (Exubera®, Nektar / Pfizer), 2006 Large active DPI; novel formulation (PulmoSol® particles) Standing cloud, MMAD 3.5 µm 2
High delivery efficiency to compensate for losses Many “firsts” for pulmonary drug delivery Withdrawn in 2007
Second inhaled insulin product (Afrezza®, MannKind), 2015 Sophisticated powder formulation (Technosphere® FDKP particles) Compact breath-actuated DPI (Dreamboat®)
Technosphere®
particles, MannKind
Dreamboat® inhaler, MannKind
Nektar Pulmonary InhalerTM
1: Patton JS et al, Adv Drug Deliv Revs 1999; 35: 235-247 2: Harper NJ et al, Diabetes Technol Ther 2007; 9 (Suppl 1): S16-S27
RELATIVE BIOAVAILABILITY AND TIME TO MAXIMUM PLASMA LEVELS (Tmax) FOR DIFFERENT INHALED INSULIN PRODUCTS
Bioavailability (%) Tmax (min) Refvs. subQ
Afrezza® 26-50 15-20 121-30 12-15 2
Exubera® 10-12 45-55 1
AIR® LPP*, Alkermes 10 45-55 1
AERx®, Aradigm 15-20 45-55 1
1: Pfüzner A and Forst T, Expert Opin Drug Deliv 2005; 2: 1097-11062: Goldberg T and Wong E, Pharmacy and Therapeutics 2015; 40: 735-741
*Large Porous Particles
THE CHALLENGE OF DELIVERING INHALED ANTIBIOTICS
Respiratory tract infections in CF and other conditions Doses typically > 100 mg: nebulizers Off-label use of nebulizers in 1980s; carbenicillen and gentamicin Patients disliked taste and smell
Tobramycin (300 mg, TOBI®, Novartis) approved 1998 Specific jet nebuliser systems recommended by regulators
4-weeks on, 4-weeks off regimen
But jet nebulizer systems inconvenient and inefficient
More convenient and efficient DPI systems: TOBI® PodhalerTM DPI + PulmoSphere® particles (Novartis)
112 mg tobramycin (4 DPI capsules)
Lung dose virtually independent of inspiratory effort
LC® Plus nebulizer, Pari
PulmoSphere® particles, Novartis
PodhalerTM DPI, Novartis
DEPOSITION OF TOBRAMYCIN BY DPI AND NEBULIZERMean data from Geller D et al; J Aerosol Med Pulm Drug Deliv 2011; 24: 175-182
150
100
50
Tobramycin deposition (mg)
Lungs Oropharynx Device Exhaled
DPI + PulmoSphere® particles (80 mg)Jet nebulizer (300 mg)
Treatment timesDPI: secondsNebulizer: minutes
Mean and SD data from Zhu B et al, Int J Pharm 2016; 514: 392-398
COMPARISON OF PODHALERTM DPI AND ORBITAL® HIGH DOSE DPI FOR DELIVERY OF PULMOSPHERE® TOBRAMYCIN
PodhalerTM DPI (Novartis): 4 x 28 mg capsules
20
100
60
40
80
Fine particle fraction (%)
Orbital® DPI (Pharmaxis): single 100 mg+ dose
NON-ADHERENCE (NON-COMPLIANCE) TO INHALATION THERAPY
Adherence: the degree to which patient behaviours coincide with the clinical recommendation of healthcare providers
Non-adherence: not taking the medication as prescribed Non-adherence is widespread Not filling prescription Taking less or more doses than prescribed May be intentional or non-intentional Contrivance: patient knows what to do, but does something else
Electronic data loggers more accurate than patient records or weighing inhalers
NON-ADHERENCE TO INHALATION THERAPY
100
80
60
40
20
1 2 3 4 5 6
Percentage underuse or overuse days
Study number
Percentage underuse days
Percentage overuse days
UNDERUSE OR OVERUSE OF INHALED STEROIDS IN SIX STUDIESFrom Cochrane M et al, Chest 2000; 117: 542-550
POOR INHALER TECHNIQUE
Using an inhaler incorrectly is very common for all inhaler types Correct technique involves preparing inhaler for use as well as
inhaling from it
pMDIs: Not firing inhaler while breathing in slowly “Cold Freon” effect
DPIs: Not inhaling hard enough Device-specific handling errors
Errors may be: Crucial Non-crucial
ADHERENCE, INHALER “COMPETENCE” AND “TRUE ADHERENCE”
Non-adherence and poor inhaler technique have similar clinical and economic consequences Variable lung dose Reduced disease control Waste of resources Need for more expensive treatment options
Has pulmonary drug delivery underachieved because of failure to solve adherence and inhaler competence issues? 1
True adherence %: (% adherence to regimen) x (% inhaler competence) / 100
Maximizing true adherence essential for successful disease management
1: Everard ML, J Aerosol Med Pulm Drug Deliv 2014; 27: A2
TACKLING NON-ADHERENCE AND POOR INHALER TECHNIQUE: EDUCATION
Management of chronic respiratory diseases:“10 % medicine, 90 % education” 1
Ensuring patients understand their illness, treatment and inhaler Healthcare professionals may not understand either
Messages need to be repeated and reinforced One-on-one; healthcare professional and patient Group sessions, internet training Written treatment plans
Switching inhalers: re-education needed Adherence: understanding and influencing patient behaviour
Addressing misconceptions, lack of trust, family dysfunction Increasing acceptability of inhalers in developing countries: social stigma
1: Fink JB, Respir Care 2005; 50: 598-600
TACKLING NON-ADHERENCE AND POOR INHALER TECHNIQUE: TECHNOLOGY
Correct inhaler selection: choose an inhaler the patient will use, and can use correctly Same inhaler to deliver multiple drugs if possible: combination inhalers Meeting patient preferences Simple DPI instructions, e.g. Open, Inhale, Close
Training aids: coordination and flow rate Dose counters Electronic data loggers
Reminders and feedback Connections to mobile phones, computers, servers
“Intelligent” inhalers: reminders, feedback, efficient delivery I-neb AAD: vibrating mesh nebulizer, controlled inhalation Potential for depositing 50 % of nebulizer fill in lungs 1
Advair® Diskus®, GSK
In-Check Flo-tone®,Clement Clarke
Propeller Sensor,Propeller Health
I-neb® AAD® nebulizer, Philips Respironics
1: Häussermann S et al, J Aerosol Med Pulm Drug Deliv 2016; 29: 242-250
SPECIAL PROBLEM GROUPS?
Very young patients Probably cannot use pMDIs, DPIs correctly
Nebulizers, pMDI plus spacers
Facemasks convenient but inefficient
Very old patients May lack inspiratory muscle strength to use DPIs
Co-morbidities
Cognitive issues
May be reassured by nebulizers
Lowest adherence in adolescents and young adults, 15-40 y 1
Intubated or ventilated patients Potential for aerosol losses in tubing
1: Morton RW and Everard ML, ISAM Textbook of Aerosol Med 2015, 925-960
“INHALATION IS BETTER”?: NOT ALWAYS
Inhaled pentamidine in HIV disease Prevention of Pneumocystis carinii pneumonia Initially (1980s) seen as effective and safe: Respirgard nebulizer Later proved to be less effective than oral therapy Effectiveness limited by inadequate delivery to poorly ventilated areas Re-occurrence of P. carinii pneumonia in lung apices
Treating solid lesions (tumours) Lung often the site of metastases Not possible to target drug with sufficient precision? May need delivery to whole of tumour, not just surface
Combination of inhaled and oral / parenteral delivery sometimes the answer?
CONCLUDING REMARKS
Successful pulmonary drug delivery presents many scientific and medical challenges
The advantages offered by pulmonary drug delivery currently considered to justify the additional complexity in many situations
The future….. Asthma and COPD: treatments evolving Topical delivery: repurposing / fulfilling unmet needs Systemic delivery: small versus larger molecules Improving bioavailability and longevity Improving true adherence: technology, education
Interest in pulmonary route seems greater than ever