PK and PD Studies for Systemic

Exposure of Locally Acting Drugs

Industry View
Lester I. Harrison, PhD
Division Scientist
3m Pharmaceuticals
Value of OINDP PK
W Systemic Absorption Systemic Exposure
W easure oI systemic saIety Ior locally
acting drugs
W PK is an Established BE etric
Standardized
Validated
Discriminating
OINDP PK Concerns
W Low Doses
W Assay LLOQ Limitations
W Variability
W ose: Drainage oI Excess Dose
W Oral Inhalation: Dosing Technique
OINDP PK Concern: Low Doses
W Low Dose Relative
Quantitatable
W Therapeutic Dose Range
ore dose options
W asal Route
ay be limited by drainage
OINDP PK Concern: Assay LLOQ
W LLOQ under 100 pg/mL common with
LC/S/S
W Commercial Availability oI Assays
Albuterol
BDP Active etabolite
Budesonide
Triamcinolone Acetonide
Cromolyn
Fluticasone Propionate?
OINDP PK Concern: Variability
W Large Inter-Subject Variability
W Large Intra-Subject Variability
W Dosing Technique
Nasal Formoterol Variability
27
Hochhaus et al, Pharmaceut Res 1992;9:291-297
asal Triamcinolone Acetonide Variability
12
Argenti et al, J Clin Pharmacol 1994;34:854-858
asal Budesonide Variability
16
Thorsson et al, Br J Clin Pharmacol 1999;47:619-624
Oral Inhalation Fluticasone Variability
12
Thorsson et al, Br J Clin Pharmacol 1997;43:155-161
#educing Variability
W Replicate Study Designs
W Increased
W asal - Reduce Dose
W Oral Inhalation - Inhalation Training
ot real world
E Limitations of OINDP PK
W o Correlation with EIIicacy
Corticosteroids
W Represents a Fraction oI Dose
Usually Less Than 30
Fine Particle Fraction?
W Summary Parameter oI Absorption
Represents outh GI First Pass Lungs
DiIIerent Rates and Extents oI Absorption
Nasal Fluticasone PK & Efficacy
280
Dose
Day 15
Symptom
Score
C
1
pg/mL
asal
200 mcg/dy
133
BKGD
Oral
5 mg/dy
212 103
Oral
10 mg/dy
194 137
Placebo 217
BKGD
Howland et al, Clin Therap 1996;18:1106-1117
Oral Inhaled Fluticasone PK & Efficacy
261
Dose
Week 6
AM FEV
1
Change, L
Symptom
Score
Cmax
pg/mL
AUC
pg/h/mL
Inhaled
200 mcg/dy
0.27 -0.17
BLQ BLQ
Inhaled
1000 mcg/dy
0.42 -0.22 116 629
Oral
20 mg/dy
-0.2 0.04 248 1230
Placebo -0.19 0.06
BLQ BLQ
Lawrence et al, Am J Respir Crit Care ed 1997;156:744-751
Value of OINDP PK: Conclusions
W PK UseIul to Establish Systemic Absorption
W ot a Surrogate Ior Local EIIicacy
W Doable
W Can Reduce Variability
W Systemic BE?
DP MDI Examples
Systemic Absorption Studies
W Formulations: DI A vs. DI B
W Study Designs
Single Dose (multiple inhalations)
Asthmatics
Crossover
Good Inhalation Technique
DP Comparative Absorption Studies
MDI A vs. MDI
W Q1 .... ...... same
W Q2 .......... same
W Particle Size Dist ... essentially same
W Spray Pattern ..... essentially same
W Valve Size ....... same
W Actuator Dimensions.. essentially same
Oral Inhaled DP PK Study 1
W Objective: Systemic Comparability
W 18 Asthmatics
W Cmax: CI 0.79 - 1.12; CV 51
W AUC: CI 0.90 - 1.35; CV 42
Oral Inhaled DP PK Study 2
W Objective: Systemic BE
W 45 Asthmatics
W Cmax
L
: CI 0.85 - 1.01; CV 30
W Cmax
H
: CI 0.80 - 0.95; CV 49
W AUC
L
; CI 0.85 - 0.95; CV 23
W AUC
H
; CI 0.86 - 0.97; CV 22
Concluded Systemic Equivalence
Ran Local Delivery Study Ior EIIicacy
DP MDI Examples
Systemic Absorption Studies
W Formulations: DI C vs. DI D
DiIIerent Strengths
Same Dose, DiIIerent umber oI PuIIs
W Study Designs
Single Dose (multiple inhalations)
Asthmatics
Crossover
Good Inhalation Technique
DP Comparative Absorption Studies
MDI C vs. MDI D
W Q1 .... ...... same
W Q2 .......... same
W Particle Size Dist ... same
W Spray Pattern ..... same
W Valve Size ....... different
W Actuator Dimensions..same
Oral Inhaled DP PK Study 3
W Objective: Systemic Comparability
W 18 Asthmatics
W Cmax: CI 0.76 - 1.00; CV 32
W AUC; CI 0.86 - 1.19; CV 37
Oral Inhaled DP PK Study 4
W Objective: Systemic BE
W 30 Asthmatics
W Cmax
L
: CI 0.82 - 1.11; CV 46
W Cmax
H
: CI 0.81 - 1.11; CV 34
W AUC
H
; CI 0.81 - 1.22; CV 37
Concluded Systemic Equivalence
Ran Local Delivery Studies on Each DI
PK Options: Charcoal lock
W Allows DiIIerentiation oI Pulmonary and
on-Pulmonary Absorbed Drug
W Utilizes Same Drug Assays and etrics
Little additional time or cost
W Do ot Have to Alter ReIerence or Test
Products
E Limitations of Charcoal lock
W o Evidence that Pulmonary Absorbed
Drug Correlates with EIIicacy
W Does ot Discriminate Potentially
Important Product DiIIerences
Oropharayngeal Deposition
Regional Lung Deposition
Very UseIul Laboratory Tool
Pulmonary Drug Absorption
Potential Surrogate Ior Local Delivery?
PK Options: Urinary Excretion
W hen PK ot Doable
W Reported Ior
Albuterol
Cromolyn
edocromil
Ipratropium
Nasal Ipratropium romide
22
W 24-Hour Urinary Excretion
10.6 I 1.9 3g (mean I SE)
CV 84
W Percent Dose Excreted
6.3 I 1.2
CV 89
ood et al, J Allergy Clin Immunol 1995;95:1111-1116
E Limitations of Urinary Excretion
W High Variability
W Low Sensitivity
Unlikely to be a Reliable Surrogate
PK Options: PD Measurement
W hen PK ot Doable
W Requires Appropriate Study Design
Dose Response Curve
Repeat Administration
E Limitations of PD
W High Variability
W Low Sensitivity
W Requires ultiple Dose Levels
DiIIicult Task iI PK ot Doable
PK Options: PK-PD
W Allows Correlation oI PK with PD
PK Linear
PD Dose Response Curve
W Increased Understanding
Systemic Exposure
Systemic SaIety
E Limitations of PK-PD
W Requires Several Dose Levels, Additional
Analyses
W Does ot Increase Ability to DiIIerentiate
Products
W Very UseIul Laboratory Tool
Development Technique
SUMMA#
W Systemic PK Assessment
eeded to Assure Systemic SaIety
Doable Ior ost Drugs
W PD, Urine Levels
ot Likely Surrogates
W Charcoal Block, PK-PD
Development Tools
FDA Question: Are There
Situations Where In Vitro Data + PK + PD
Can e #elied on to Assure Local Efficacy
W an Be Relied On To Assure Implies Predictability
Beta-Agonists
Corticosteroids
Cromolyn
Anticholinergics
Antihistamines
W Solutions?
eed Ior Caution Until Predictability
Demonstrated