1. PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSURE OF ORALLY INHALED AND NASAL DRUGS
Venkata Ramana S. Uppoor, M.Pharm., Ph.D., R.Ph.
Division of Pharmaceutical Evaluation - II
Office of Clinical Pharmacology & Biopharmaceutics
Center for Drug Evaluation & Research, FDA
Good afternoon
I would like to thank the AAPS organizing committee and Dr. Oakley for inviting me to give this presentation.

2. Outline Why oral inhalation and nasal delivery
Why pharmacokinetics (PK)
Examples of locally acting drug products
Examples of systemically acting drug products
Difficulties with PK for nasal & inhalation products
Summary

3. Why nasal and oral inhalation delivery
LOCAL ACTION:
Alternate route of administration of drugs
Intention is to minimize systemic exposure
Generally faster onset of action
Convenience
SYSTEMIC ACTION:
Rapid absorption, higher bioavailability - Lower dose needed
Avoidance of metabolism & irritation in GIT

4. Approaches to establish bioavailability/bioequivalence
21 CFR : In descending order of accuracy, sensitivity and reproducibility:
Pharmacokinetic studies
Pharmacodynamic studies
Well-controlled clinical trials
In vitro tests
Any other approach deemed adequate by FDA

5. In vitro
Clinical efficacy/safety
Pharmacokinetics
Pharmacodynamics

6. Why not BA/BE based on PK alone
Systemic exposure data represents safety for locally acting drug products
To address efficacy issues - also need clinical data

7. Fate of inhaled drug products
Amount reaching systemic circulation = pulmonary + oral (GI) BA fractions
Ref: American J. Of Respiratory & Critical Care Medicine, 03/98, vol. 157, 3 (2), 7-244

8. Inhalation PK with charcoal block
Administration of activated charcoal with some inhaled drugs can block the absorption from GIT
Systemic drug concentrations with charcoal block represent absorption via respiratory tract
Useful in comparing relative dose delivery to lung from different formulations
Does not address
Regional lung deposition
Oropharyngeal deposition

9. Lung deposition - Gamma scintigraphy
Drug delivery to a local site assessed via in vivo imaging
99m Technetium used as a radiolabel
Some current concerns
Labeled drug may have altered aerodynamics
Signal attenuation due to body tissue
Unclear definition of clinically relevant biospace
Possible lab-to-lab variation

10. Nasal Guidance
Guidance for Industry: Bioavailability & Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action
BA & BE - Product quality
Nasal solution products - In vitro data only
Nasal suspension products
In vitro data
Clinical studies for local delivery
Systemic absorption studies
Pharmacokinetics
Pharmacodynamics
BA - PK/PD/Clinical

11. Decision tree for in vivo product quality BA/BE studies for nasal products
Is the formulation
a suspension?
No in vivo studies for
solution formulations NO
Conduct clinical study for
local delivery
Conduct PD/clinical study
for systemic absorption
YES NO
Is a PK study
feasible?
Conduct clinical study for
local delivery
Conduct PK study for
systemic exposure
YES

12. Albuterol metered dose inhaler
Pharmacodynamics (PD)
FDA Draft Guidance

13. Nasal Guidance - PK recommendations
PK study for systemic exposure
Single or multiple dose
Nonreplicate or replicate design
Healthy subjects or patients
Number of doses may exceed labeled dose (loss of drug should be minimized)
* Additional pilot study recommended

14. Examples of locally acting nasal products

15. Examples of systemically acting nasal products

16. Study designs used in these examples
Crossover
Parallel
Different dose levels
Single dose &/or multiple dose

17. PK studies: Issues Low dose Assay sensitivity Variability
Limitations of volume/dose : 25 to 200 mL - excess volume may lead to drainage to outside or to oropharyngeal region

18. PK studies: Feasibility
Several antihistamines
Systemically acting drugs
Some steroids

19. Examples of oral inhalation products

20. Study designs used in these examples
Crossover
Parallel
Different dose levels
Single dose &/or multiple dose

21. PK studies: Issues Low dose Assay sensitivity Variability
Feasibility of administering multiple puffs/dose

22. PK studies: Feasibility
Some beta agonists
Most corticosteroids
Systemically acting drugs

23. SYSTEMIC ABSORPTION WITH PK
PHARMACODYNAMICS

24. Summary
Pharmacokinetic studies are the first choice to characterize systemic exposure of nasal and oral inhalation products. However, difficulties may be encountered in using PK for documentation of bioavailability/bioequivalence for some locally acting nasal and oral inhalation drug products. In those cases, pharmacodynamic data need to be used to characterize the systemic absorption