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.

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

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

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

In vitro Clinical efficacy/safety Pharmacokinetics Pharmacodynamics

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

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

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

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

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

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

Albuterol metered dose inhaler Pharmacodynamics (PD) FDA Draft Guidance

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

Examples of locally acting nasal products

Examples of systemically acting nasal products

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

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

PK studies: Feasibility Several antihistamines Systemically acting drugs Some steroids

Examples of oral inhalation products

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

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

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

SYSTEMIC ABSORPTION WITH PK PHARMACODYNAMICS

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