PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSURE OF ORALLY INHALED AND NASAL DRUGS

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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

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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

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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

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Approaches 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

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In vitro
Clinical efficacy/safety
Pharmacokinetics
Pharmacodynamics
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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

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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
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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

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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

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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

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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
NO
YES
Is a PK study feasible?
Conduct clinical study for local delivery Conduct
PK study for systemic exposure
YES
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Albuterol metered dose inhaler

• Pharmacodynamics (PD)
• FDA Draft Guidance

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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

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Examples of locally acting nasal products
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Examples of systemically acting nasal products
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Study designs used in these examples

• Crossover
• Parallel
• Different dose levels
• Single dose /or multiple dose

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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

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PK studies Feasibility

• Several antihistamines
• Systemically acting drugs
• Some steroids

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Examples of oral inhalation products
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Study designs used in these examples

• Crossover
• Parallel
• Different dose levels
• Single dose /or multiple dose

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PK studies Issues

• Low dose
• Assay sensitivity
• Variability
• Feasibility of administering multiple puffs/dose

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PK studies Feasibility

• Some beta agonists
• Most corticosteroids
• Systemically acting drugs

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SYSTEMIC ABSORPTION WITH PK
PHARMACODYNAMICS
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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