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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

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pk and pd studies for systemic exposure of locally acting drugs industry view

PK and PD Studies for Systemic Exposure of Locally Acting DrugsIndustry View

Lester I. Harrison, PhD

Division Scientist

3m Pharmaceuticals

value of oindp pk
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
OINDP PK Concerns
  • Low Doses
  • Assay LLOQ Limitations
  • Variability
  • Nose: Drainage of Excess Dose
  • Oral Inhalation: Dosing Technique
oindp pk concern low doses
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
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
OINDP PK Concern: Variability
  • Large Inter-Subject Variability
  • Large Intra-Subject Variability
  • Dosing Technique
nasal formoterol variability n 27
Nasal Formoterol VariabilityN = 27

Hochhaus et al, Pharmaceut Res 1992;9:291-297

nasal triamcinolone acetonide variability n 12
Nasal Triamcinolone Acetonide VariabilityN = 12

Argenti et al, J Clin Pharmacol 1994;34:854-858

nasal budesonide variability n 16
Nasal Budesonide VariabilityN = 16

Thorsson et al, Br J Clin Pharmacol 1999;47:619-624

oral inhalation fluticasone variability n 12
Oral Inhalation Fluticasone VariabilityN = 12

Thorsson et al, Br J Clin Pharmacol 1997;43:155-161

reducing variability
Reducing Variability
  • Replicate Study Designs
  • Increased N
  • Nasal - Reduce Dose
  • Oral Inhalation - Inhalation Training
    • Not real world
be limitations of oindp pk
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 efficacy n 280
Nasal Fluticasone PK & EfficacyN = 280

Howland et al, Clin Therap 1996;18:1106-1117

oral inhaled fluticasone pk efficacy n 261
Oral Inhaled Fluticasone PK & EfficacyN = 261

Lawrence et al, Am J Respir Crit Care Med 1997;156:744-751

value of oindp pk conclusions
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
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 studies mdi a vs mdi b
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
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
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 studies1
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 studies mdi c vs mdi d
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
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
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
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
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
PK Options: Urinary Excretion
  • When PK Not Doable
  • Reported for
    • Albuterol
    • Cromolyn
    • Nedocromil
    • Ipratropium
nasal ipratropium bromide n 22
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
BE Limitations of Urinary Excretion
  • High Variability
  • Low Sensitivity
  • Unlikely to be a Reliable Surrogate
pk options pd measurement
PK Options: PD Measurement
  • When PK Not Doable
  • Requires Appropriate Study Design
    • Dose Response Curve
    • Repeat Administration
be limitations of pd
BE Limitations of PD
  • High Variability
  • Low Sensitivity
  • Requires Multiple Dose Levels
  • Difficult Task if PK Not Doable
pk options pk pd
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
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
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
slide34
FDA Question: Are There Situations Where In Vitro Data + PK + PD Can Be Relied on to Assure Local Efficacy
  • Can Be Relied On To Assure Implies Predictability
    • Beta-Agonists
    • Corticosteroids
    • Cromolyn
    • Anticholinergics
    • Antihistamines
  • Solutions?
  • Need for Caution Until Predictability Demonstrated