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

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

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

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

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

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 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

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

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

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

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

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

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

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

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”

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

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.