Title: PHARMACOKINETIC STUDIES FOR ORAL INHALATION AEROSOLS AND NASAL SPRAYS - CURRENT FDA PRACTICES
1PHARMACOKINETIC 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
2Outline
- 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
3Pharmacokinetics/BiopharmaceuticsClinical
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
4Pharmacokinetics/BiopharmaceuticsClinical
Pharmacology (General requirements for NMEs)
(continued)
- Clinical Pharmacology
- 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
6Approaches to establish bioavailability/bioequival
ence
- 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
7Fate 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
8Why 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
9PK 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
10Inhalation 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
11Lung 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
12New 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
13Role 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
14Switch 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
15Summary
- 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
16Summary (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.