PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSURE OF ORALLY INHALED AND NASAL DRUGS

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

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 • Generally faster onset of action • Convenience

4. Approaches to establish bioavailability/bioequivalence 21 CFR 320.24: 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