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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
• Systemic Absorption = Systemic Exposure
• Measure of systemic safety for locally acting drugs
• PK is an Established BE Metric– Standardized– Validated– Discriminating
OINDP PK Concerns
• Low Doses
• Assay LLOQ Limitations
• Variability
• Nose: Drainage of Excess Dose
• Oral Inhalation: Dosing Technique
OINDP PK Concern: Low Doses
• “Low” Dose Relative– Quantitatable
• Therapeutic Dose Range– More dose options
• Nasal Route– May be limited by drainage
OINDP PK Concern: Assay LLOQ
• LLOQ under 100 pg/mL common with LC/MS/MS
• Commercial Availability of Assays– Albuterol– BDP + Active Metabolite– Budesonide– Triamcinolone Acetonide– Cromolyn– Fluticasone Propionate?
OINDP PK Concern: Variability
• Large Inter-Subject Variability
• Large Intra-Subject Variability
• Dosing Technique
Reducing Variability
• Replicate Study Designs
• Increased N
• Nasal - Reduce Dose
• Oral Inhalation - Inhalation Training– Not real world
BE Limitations of OINDP PK
• No Correlation with Efficacy– Corticosteroids
• Represents a Fraction of Dose– Usually Less Than 30%– Fine Particle Fraction?
• Summary Parameter of Absorption– Represents Mouth + GI + First Pass + Lungs– Different Rates and Extents of Absorption
Nasal Fluticasone PK & EfficacyN = 280
DoseDay 15
SymptomScore
C1
pg/mL
Nasal200 mcg/dy
133 BKGD
Oral5 mg/dy
212 103
Oral10 mg/dy
194 137
Placebo 217 BKGD
Howland et al, Clin Therap 1996;18:1106-1117
Oral Inhaled Fluticasone PK & EfficacyN = 261
DoseWeek 6
AM FEV1
Change, LSymptomScore
Cmaxpg/mL
AUCpg/h/mL
Inhaled200 mcg/dy
0.27 -0.17 BLQ BLQ
Inhaled1000 mcg/dy
0.42 -0.22 116 629
Oral20 mg/dy
-0.2 0.04 248 1230
Placebo -0.19 0.06 BLQ BLQ
Lawrence et al, Am J Respir Crit Care Med 1997;156:744-751
Value of OINDP PK: Conclusions
• PK Useful to Establish Systemic Absorption
• Not a Surrogate for Local Efficacy
• Doable
• Can Reduce Variability
• Systemic BE?
BDP MDI Examples Systemic Absorption Studies
• Formulations: MDI A vs. MDI B
• Study Designs– Single Dose (multiple inhalations)– Asthmatics– Crossover– Good Inhalation Technique
BDP Comparative Absorption StudiesMDI A vs. MDI B
• Q1 …….. ……………… same
• Q2 ………………………… same
• Particle Size Dist ……… essentially same
• Spray Pattern …………… essentially same
• Valve Size …..………… same
• Actuator Dimensions…… essentially same
Oral Inhaled BDP PK Study 1
• Objective: Systemic Comparability
• N = 18 Asthmatics
• Cmax: CI = 0.79 - 1.12; CV = 51%
• AUC: CI = 0.90 - 1.35; CV = 42%
Oral Inhaled BDP PK Study 2
• Objective: Systemic BE
• N = 45 Asthmatics
• CmaxL: CI = 0.85 - 1.01; CV = 30%
• CmaxH: CI = 0.80 - 0.95; CV = 49%
• AUCL; CI = 0.85 - 0.95; CV = 23%
• AUCH; CI = 0.86 - 0.97; CV = 22%
Concluded Systemic Equivalence Ran Local Delivery Study for Efficacy
BDP MDI Examples Systemic Absorption Studies
• Formulations: MDI C vs. MDI D– Different Strengths– Same Dose, Different Number of Puffs
• Study Designs– Single Dose (multiple inhalations)– Asthmatics– Crossover– Good Inhalation Technique
BDP Comparative Absorption StudiesMDI C vs. MDI D
• Q1 …….. ……………… same
• Q2 ………………………… same
• Particle Size Dist ……… same
• Spray Pattern …………… same
• Valve Size …..………… different
• Actuator Dimensions……same
Oral Inhaled BDP PK Study 3
• Objective: Systemic Comparability
• N = 18 Asthmatics
• Cmax: CI = 0.76 - 1.00; CV = 32%
• AUC; CI = 0.86 - 1.19; CV = 37%
Oral Inhaled BDP PK Study 4
• Objective: Systemic BE• N = 30 Asthmatics
• CmaxL: CI = 0.82 - 1.11; CV = 46%
• CmaxH: CI = 0.81 - 1.11; CV = 34%
• AUCH; CI = 0.81 - 1.22; CV = 37%
Concluded Systemic Equivalence Ran Local Delivery Studies on Each MDI
PK Options: Charcoal Block
• Allows Differentiation of Pulmonary and Non-Pulmonary Absorbed Drug
• Utilizes Same Drug Assays and Metrics – Little additional time or cost
• Do Not Have to Alter Reference or Test Products
BE Limitations of Charcoal Block
• No Evidence that Pulmonary Absorbed Drug Correlates with Efficacy
• Does Not Discriminate Potentially Important Product Differences– Oropharayngeal Deposition– Regional Lung Deposition
Very Useful Laboratory Tool– “Pulmonary” Drug Absorption– Potential Surrogate for Local Delivery?
PK Options: Urinary Excretion
• When PK Not Doable
• Reported for– Albuterol– Cromolyn– Nedocromil– Ipratropium
Nasal Ipratropium BromideN = 22
• 24-Hour Urinary Excretion
10.6 1.9 g (mean SE)
CV = 84%
• Percent Dose Excreted
6.3 1.2%
CV = 89%
Wood et al, J Allergy Clin Immunol 1995;95:1111-1116
BE Limitations of Urinary Excretion
• High Variability
• Low Sensitivity
Unlikely to be a Reliable Surrogate
PK Options: PD Measurement
• When PK Not Doable
• Requires Appropriate Study Design– Dose Response Curve– Repeat Administration
BE Limitations of PD
• High Variability
• Low Sensitivity
• Requires Multiple Dose Levels
Difficult Task if PK Not Doable
PK Options: PK-PD
• Allows Correlation of PK with PD– PK Linear– PD Dose Response Curve
• Increased Understanding – Systemic Exposure– Systemic Safety
BE Limitations of PK-PD
• Requires Several Dose Levels, Additional Analyses
• Does Not Increase Ability to Differentiate Products
• Very Useful Laboratory Tool
Development Technique
SUMMARY
• Systemic PK Assessment – Needed to Assure Systemic Safety– Doable for Most Drugs
• PD, Urine Levels – Not Likely Surrogates
• Charcoal Block, PK-PD– Development Tools