1. PHARMACOKINETIC STUDIES FOR ORAL INHALATION AEROSOLS AND NASAL SPRAYS - CURRENT FDA PRACTICES
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

2. Outline General BA/PK studies needed for a new molecular entity
How to generally assess BA/BE
Methods and issues in assessing BA/BE for locally acting drug products
Role of systemic PK & PD studies for product changes

3. Pharmacokinetics/Biopharmaceutics Clinical Pharmacology (General requirements for NMEs as inhalation/nasal products)
Pharmacokinetics/Biopharmaceutics:
Mass Balance studies with radiolabeled drug
Single and multiple dose pharmacokinetics
Absolute bioavailability/relative bioavailability
Dose proportionality
Bioequivalence studies to establish the link between the market and clinical products

4. Pharmacokinetics/Biopharmaceutics Clinical Pharmacology (General requirements for NMEs) (continued)
Pharmacokinetics in the target population
Special population studies
Age, Gender, Race, etc.
Disease states such as renal and hepatic impairment
In vitro metabolism/drug interactions
In vivo drug interaction studies
Establishment of pharmacokinetic/ pharmacodynamic correlations

5. Bioavailability is an important factor in the performance and quality of a dosage form and can have a major impact on the safety and efficacy of a drug product. It is also useful to understand the in vivo characteristics of a drug
In vitro testing alone for some drugs is not sufficient to establish that a drug product will have adequate bioavailability

6. 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
Emphasis and order of importance of each of these types of studies will depend on whether the products are intended for local or systemic action & whether they are solutions or suspensions

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

9. PK studies for locally acting, orally inhaled drug products
General conventional Clinical Pharmacology & Biopharmaceutics studies, such as SD, MD, dose proportionality & PK/PD studies
These studies may also be needed in the patient population if drug delivery is expected to be different

10. 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 (delivery to relevant biospace)
Oropharyngeal deposition

11. 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

12. New oral inhalation products
In addition to conventional pharmacokinetic studies
Clinical studies
Pharmacodynamic studies for safety
Population PK/PD studies as appropriate
* Topical vs. systemic effect studies, where applicable
and specific topical claim is sought

13. Role of systemic PK and PD studies for locally acting, orally inhaled drug products
For certain minor changes to a well-characterized product, systemic PK/PD and in vitro data may be sufficient
For most changes, systemic PK/PD used as supportive, in addition to clinical PD/clinical trials
In specific cases, need to contact the Division of Pulmonary & Allergy Drug Products

14. Switch programs For e.g., from CFC based to non-CFC based
Clinical and pharmacodynamic studies
Pharmacokinetic studies
Refer to the Division of Pulmonary and Allergy Drug Products - Points to Consider document “Clinical development programs for MDI and DPI drug products”

15. Summary
BA/BE studies are necessary to understand the in vivo characteristics of the drug (clinical pharmacology/pharmacokinetics) and the drug product (product quality)
BA/BE characterization for orally inhaled and nasal products can be accomplished using in vitro/PK/PD/clinical studies

16. Summary (continued)
Pharmacokinetic studies are the first choice to characterize systemic exposure of nasal and oral inhalation products. However, use of PK for documentation of bioavailability/bioequivalence for locally acting nasal and oral inhalation drug products is generally not adequate. In those cases, pharmacodynamic data are needed to characterize the delivery to the site of action.