Contents General considerations for pulmonary drugs Case Study - Proventil-HFA Case Study – QVAR...
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Transcript of Contents General considerations for pulmonary drugs Case Study - Proventil-HFA Case Study – QVAR...
P r e c l i n i c a l d e v e l o p m e n t c o n s i d e r a t i o n s f o r t h e p u l m o n a r y d e l i v e r y o f d r u g s a p p r o v e d b y o t h e r r o u t e s
C h e t L e a c h
L i f e S c i e n c e s R e s e a r c h a n d D e v e l o p m e n t
Contents
• General considerations for pulmonary drugs • Case Study - Proventil-HFA• Case Study – QVAR• Lung delivery of peptides/proteins• Lung delivery of i.v. antibiotics• Conclusions
General Preclinical Considerations
Has the drug been to the site before?
Is the local concentration at the new site higher than before?
Are the usual metabolic pathways present in the new site?
Are there new susceptible cell types (e.g. growth factor issues)?
Will new or existing excipients cause problems (e.g. bronchospasm, membrane disruptors)?
Will neutralizing or anaphylactic antibodies form?
Proventil HFATM (AiromirTM) versus Albuterol CFC
Same drug, different propellant
Same amount of drug delivered
Same particle size distribution
Improved dosing characteristics
Proventil HFA
Ventolin
Proventil-HFAPreclinical Program
(registered in 40 countries) Inhalation range-finding study in rats
Inhalation range-finding in dogs
28-Day inhalation study in rats
28-Day inhalation study in dogs
90-day inhalation study in rats
Inhalation teratology study in rats
Clinical Efficacy Study
Proventil HFA Preclinical Conclusions•No preclinical surprises in two species•No PK/ADME clinical surprises•No efficacy surprises
• SO no further preclinical studies necessary
QVARTM (HFA-BDP) versus CFC-Beclomethasone (CFC-BDP)
Same drug, different propellant
Different amount of drug delivered
Different particle size distribution
Improved dosing characteristics
Human Deposition Pattern
QVAR
31% 94%Oral
Lung
59% 4%
CFC-BDP
8% 1%Exhaled
1.1 microns 3.5 microns
QVARPreclinical Program
(registered in 40 countries) Inhalation range-finding study in rats
Inhalation range-finding in dogs
14-Day inhalation study in rats
14-Day inhalation study in dogs
12-month inhalation study in dogs
Inhalation teratology study in rats
PharmacokineticsModel predictions for QVAR
Mucocilaryclearance
Projected Serum Levels Based on Deposition Results
Beclovent - 100a QVAR - 100a
Oral depositionb 95g 20g 30g 6gc
Lung depositionb 5g 5g 60g 60g
Serum Total 25g 66g
Ratio 1 2.6:
a assumes 100g of beclomethasone dipropionate is delivered to the patientb assumes an oral bioavailability of 21% and a lung bioavailability of 100%c the formula represents amount deposited serum based on bioavailability
Phase 1 Clinical StudySerum Concentrations of BDP After
Single Inhaled Doses
0
200
400
600
800
0 5 10 15 20 25 30
Time Post Initial Inhalation (hours)
Ser
um B
eclo
met
haso
ne
Con
cent
rati
on (
pg/m
l)
200 mcg HFA-BDP400 mcg CFC-BDP
Regression analysis of change from baseline in FEV1 as % predicted at
week 626
24
14
16
18
20
22
100 400 800150
CFC-BDP
Qvar
Total daily dose (mcg/day)
Relative dose ratio 2.6(95% CI 1.1-11.6)
2.6
Change from baseline in FEV1 as % predicted
Long-term asthma control:breakthrough asthma following 2:1
switch
HFA-BDPCFC-BDP
0
20
40
60
80
100
Day1
Wk4
Wk8
Mth4
Mth6
Mth8
Mth 10
Mth12
% patients with no asthma related adverse events
Kaplan Meier plot
Urinary Free Cortisol:Percentage change from baseline in 24hr UFC
-100
-80
-60
-40
-20
0
20
40
60
80
100
HFAPlacebo
HFA BDP200 mcg
HFA BDP400 mcg
HFA BDP800 mcg
CFC BDP800 mcg
Percentagechangefrombaseline in24hr UFC
* **
* Indicates significant mean difference from Placebo
QVARPreclinical Conclusions•No preclinical surprises in two species•No PK/ADME clinical surprises•No efficacy surprises
• SO no further preclinical studies necessary
Proteins/Peptides There are numerous peptides with
significant therapeutic activity in every field of medicine
BUT, they have serious delivery problems– Need to inject
– Time of action too short
– Native structures too susceptible to peptidases
Local Lung versus Systemic Delivery
• Rule of thumb is that 2-5% of the i.v. dose reaches the lungs
• The other 95% adds to unwanted side-effects
Natural Human Bioavailability of Insulin
Based on various published studies
30
25
20
15
10
5
0Oral Nasal Pulmonary
Bioavailability
relative to
SC injection
(%)
InsulinPreclinical / Clinical Issues
Insulin is present in virtually every cell
Larger local lung concentrations than previously seen
Insulin is a growth factor
Insulin by any route induces antibody formation
Leuprolide
Analog of LHRH
Treatment of endometriosis
Treatment of prostate cancer
Side effects inhibit its use
Leuprolide PulmoSphere™ DPI
0.01
0.1
1
10
100
0 4 8 12 16 20 24
Time postdose (hr)
Ser
um
leu
pro
lide
(ng
/ml)
IV
INHL
iiiii
PulmoSphere
Particles
22 µ µmm•Hollow•Porous•Ultra low density
Self-Assembling Structures in Water
LeuprolidePreclinical / Clinical Issues
Larger local lung concentrations than previously seen
Antibody question
DSPC, DPPC excipients
(normal components of lung surfactant)
0
100
200
300
400
0
20
40
5001000150020002500
0 2 4 6 8 10 12 14
0
100
200
Pla
sm
aC
onc
(ng/m
L)
Time After Dosing (hr)
Plasma
Lavag
eC
onc
(ng/m
L)
Lung
LavageInhalation IVMean InhalationMean IV
Lun
gC
onc
( g/g
)
Inhalation versus i.v. of Antibiotic A in rats
Antibiotic A inhalation in Dogs
0
100
200
300
400
500
600
700
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
0
10
20
30
40
50
Low Dose Mid Dose High Doseng
/ m
L P
lasm
a
Time After Start of Dosing (days)
Plasma t1/2 = 28 hours
Day 1 Day 14 Day 29
g/g
Lun
gA
nti
bio
tic
Co
nce
ntr
atio
n
Lung Tissue t1/2 = 19 days
•4 orders of magnitude delta between lung and plasma
•Plasma likely to be undetectable at doses targeting MICs in lung
Phase-1 Clinical Study of Antibiotic B
0
0.2
0.4
0.6
0.8
0 4 8 12 16 20 24
Hours (time after end of inhalation)
Se
rum
An
tib
ioti
c B
(u
g/m
l)
PulmoSphere Antibiotic B, 85 mg
Nebulized Antibiotic B, 300 mg
Antibiotic B in Humans
Minutes to Dose
Dry Powder Nebulizer
0
2
4
6
8
10
12
14
16
Summary A route change to inhalation can offer:
– Faster onset
– Higher bioavailability
– Freedom from injections
– Less side effects
Preclinical requirements should be unique to each new change in route
Preclinical programs should stress the exploration of known differences, not unsubstantiated speculation
The fear of unknown and/or unreasonable preclinical and clinical requirements keeps many new routes for drug administration economically unattractive (especially for non-blockbuster category drugs)
Future Biotech Inhalers
Insulin
Growth factors (local & systemic)
Interferons
Lung surfactants
Monoclonal antibodies
Receptors
Viral vectors