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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. Outline.

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pharmacokinetic testing for systemic exposure of orally inhaled and nasal drugs

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

outline
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
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
approaches to establish bioavailability bioequivalence
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
slide5

In vitro

Clinical efficacy/safety

Pharmacokinetics

Pharmacodynamics

why not ba be based on pk alone
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
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
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
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
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
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
Albuterol metered dose inhaler
  • Pharmacodynamics (PD)
  • FDA Draft Guidance
nasal guidance pk recommendations
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

study designs used in these examples
Study designs used in these examples
  • Crossover
  • Parallel
  • Different dose levels
  • Single dose &/or multiple dose
pk studies issues
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
PK studies: Feasibility
  • Several antihistamines
  • Systemically acting drugs
  • Some steroids
study designs used in these examples20
Study designs used in these examples
  • Crossover
  • Parallel
  • Different dose levels
  • Single dose &/or multiple dose
pk studies issues21
PK studies: Issues
  • Low dose
  • Assay sensitivity
  • Variability
  • Feasibility of administering multiple puffs/dose
pk studies feasibility22
PK studies: Feasibility
  • Some beta agonists
  • Most corticosteroids
  • Systemically acting drugs
summary
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