# Presentation: 781695

## 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

## Nasal Formoterol VariabilityN = 27

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

## Nasal Triamcinolone Acetonide Variability N = 12

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

## Nasal Budesonide Variability N = 16 

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

## Oral Inhalation Fluticasone Variability N = 12 

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

## 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 & EfficacyN = 280

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

## Oral Inhaled Fluticasone PK & EfficacyN = 261

- 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 StudiesMDI 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 StudiesMDI 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 BromideN = 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

## 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