Post on 21-Jun-2015
description
Evaluation of the AERx System for the Pulmonary Delivery of
Recombinant Human Interferon alfa-2b to Healthy Subjects
Gul Balwani, Brooks Boyd, John Whatley, John Thipphawong, Richard Morishige, Jerry Okikawa, Babatunde Otulana, Emmanuel Tamchès, Thierry Buclin, Jerome Biollaz, François Spertini, Igor Gonda
CRS Meeting July 23, 2002
Introduction
• rH Interferon alfa-2b (MW of 19,265 Da)
• Specific activity = 2.6 x 10 8 IU/mg
• Indications
– Hepatitis B and C Infection
– Various cancers (Hairy cell leukemia, Malignant Melanoma, Follicular
Lymphoma)
• Therapy
– Chronic parenteral administration for at least six months
• Doses
– Hep. C: 3 MIU 3x/week
– Hep. B: 10 MIU 3x/week or 5 MIU/day
Advantages of Using AERx for Delivery of Interferon Alfa
• Non-invasive convenient therapy which should improve patient
compliance.
• Precise, reliable and efficient dosing similar to subcutaneous
injections.
CMC Goals
• Systemic Dose
• Blister Contents
• Fill Volume
• Target Concentration
• Stability
3-4 million units/dosage form
250 g or 65 million units
45 microliters
5.56 mg/ml
> 6 months at 5o C
Component Amount per DF Amount per ml
rH INF -2b, EP 0.2500 mg* 5.56 mg* Na2 HPO4 . 7 H2 O, USP Na H2 PO4 . 2 H2 O, USP
0.2613 mg 0.0234 mg
5.81 mg 0.52 mg
Polysorbate 20, NF 0.0450 mg 1.00 mg WFI, USP q.s. ad 45 L q.s. ad 1.0 ml
*Actual quantity weighed depends on the chemical assay Final pH adjusted to 7.5 using 25 mM solution of Na2 HPO4 / Na H2 PO4
Fill volume = 45 2.25 L ( 5 %)
Formulation Composition
Clinical Release Test Results
• Content uniformity: 99.9 % LC , 3.5 % RSD
• pH: 7.4
• Dimers: Less than limit of detection (0.1%)
• Emitted Dose & EDU: 65.9 %, 4.3 % RSD
• PSD: 2 μm MMAD, 1.35 GSD, 97 % FPF
• Endotoxin: < 0.6 EU/ml
• MLT: < 1 CFU/ml and absence of indicator organisms
• Bioassay: 1452 MIU/ml (65.34 MIU/DF)
Calculated Dose Levels
Label Claim: 250 μg/DF DF’s
Extrusion Contents (μg) (MIU)
Emitted Dose (μg) (MIU)
FPD (Lung Dose) (μg) (MIU)
1 Partial 250 65 47 12.2 46 12 1 Full 250 65 150 39 146 38 2 Full 500 130 300 78 291 76
65 MIU/DF is based on specific activity of 260 MIU/mg
Clinical Study
A Single-Center, Open-Label, Dose Escalation Study to
Compare the Safety, Pharmacokinetics, and
Pharmacodynamics of Subcutaneous and Inhaled Interferon
‑2b [IFN -2b] in Healthy Volunteers
Study Design (1)
Subjects Part A
SC Intron A Partial Dose 1 Blister 2 Blisters
3 10 MIU 46 mcg/12 MIU
3 10 MIU 146 mcg/38 MIU
8 10 MIU 291 mcg/76 MIU
Part B (Lung Dose using AERx)
Clinical Site: Hospital Beaumont, Lausanne, Switzerland
Sponsor: Aradigm Corp.
Washout period = 10 days
Study Design (2)
Blood Samples
• PK: 3 days (0, 30m, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 hrs).
• PD: 2 weeks (0, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168 hrs).
Endpoints
• PK – IFN 2b
• PD – 2’ 5’-AS, 2 microglobulin, neopterin
Study Design (3)
Safety
1. Methacholine challenge
(screening & end of study)
2. Pulmonary Function Tests (PFT)
(0, 30m, 60m, 90m, 3, 6 hrs. & end of study)
3. Labs: Hematology, biochemistry, urinalysis
(screening & end of study)
4. Adverse experiences
Results - Subjects
• 15 received IFN -2b SC (38.5 μg/10 MIU)
• 13 received AERx IFN -2b & completed Part B
(2 subjects dropped out after Part A)
• AERx IFN -2b
Dose n
46 μg/12 MIU 2
146 μg/38 MIU 3
291 μg/76 MIU 8
Results - Safety Summary
1. Adverse Events
41(33 mild, 8 moderate) after SC
22 (all mild) after AERx
2. No SAEs
3. ECG – no clinically relevant changes
4. Vitals – low grade fever in all groups (< 10 hours)
5. Lab – small variation in monocyte/lymphocyte count and
transaminases (expected after SC)
PK Results
0
10
20
30
40
50
60
70
80
90
0 6 12 18 24 30 36 42 48 54 60 66 72
Theoric_time (hr)
meandataIntronA10 MIU.pwo
Error
meandata inhaled EP2001 22.5MIU dose.pwo
Error
meandata inhaled EP2001 75MIU dose.pwo
Error
meandata inhaled EP2001 150MIU dose.pwo
Error
SC: 38 g (10 MIU)
Inhaled: 46 g (12 MIU)
Inhaled: 146 g (38 MIU)
Inhaled: 291 g (76 MIU)
Time (hr)
PK Results
Mean
PK
Parameter
SC
10 MIU
(%CV)
n=13
AERx
12 MIU
(%CV)
n=1
AERx
38 MIU
(%CV)
n=3
AERx
76 MIU
(%CV)
n=8
C max (IU/ml)
T max (h)
AUC 0-inf (h.IU/ml)
Frel to SC (%)
64
(37%)
6.8
(19%)
665
(40%)
-
3
10
34
ND
19
(20%)
10
(0%)
302
(38%)
12
35
(41%)
8.8
(21%)
514
(48%)
10
PD Results – β2 microglobulin
0.0
0.5
1.0
1.5
2.0
2.5
0 24 48 72 96 120 144 168
Time (hr)
meanb2-micro data 10 MIU intronA.pwo
Error
meanb2-micro data 150 MIU.pwo
Error
meanb2-micro data 75 MIU.pwo
Error
meanb2-micro data 22.5 MIU.pwo
Error
SC: 38 g (10 MIU)
Inhaled: 291 g (76 MIU)
Inhaled: 146 g (38 MIU)
Inhaled: 46 g (12 MIU)
PD Results – 2-5AS
0
500
1000
1500
2000
2500
0 24 48 72 96 120 144 168
Time (hr)
mean 2-5AS data 10 MIU IntronA.pwo
Error
mean 2-5ASdata 150 MIU.pwo
Error
mean 2-5AS data 75 MIU.pwo
Error
mean 2-5AS data 22.5 MIU.pwo
Error
SC: 38 g (10 MIU)
Inhaled: 291 g (76 MIU)
Inhaled: 146 g (38 MIU)
Inhaled: 46 g (12 MIU)
Relationship Between Inhaled Doses and
Corresponding AUC
y = 1.9236x - 26.36
R2 = 0.9704
0100200300400500600700
0 100 200 300 400
Lung Dose (mcg)
AU
C (0
to in
f)
Conclusions
• AERx IFN bioavailability is 10-12 % relative to IFN SC.
• PD response was found to be similar for all doses of AERx IFN and 10 MIU
of IFN given SC thereby allowing lower dosing by pulmonary route.
• Lower incidence and severity of adverse events by the pulmonary route
compared to SC.
– Local skin reaction seen by SC can be eliminated by pulmonary route.
• AERx intersubject variability similar to SC.
Acknowledgements
• Aradigm Corporation, Hayward, CA
– Dr. Stephen Farr, VP Research & Development
– Beth Mallory
– Evelyn Gabatan
– Christine Inose
– Lawrence Linn
• Division of Clinical Pharmacology, CHUV, Lausanne, Switzerland
• Division of Immunology and Allergy, CHUV, Lausanne, Switzerland
• Triskel Integrated Services, Geneva, Switzerland