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1、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,Why oral inhalation and na
2、sal 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 m
3、inimize 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,21 CFR
4、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,Pharmacokinetics,Pharmacodynamics,Clinical efficacy/safety,In vitro,Why not BA/BE based o
5、n 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,
6、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 lun
7、g 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
8、 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
9、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
10、 for solution formulations,Conduct clinical study for local delivery Conduct PD/clinical study for systemic absorption,Is a PK study feasible?,NO,NO,YES,YES,Conduct clinical study for local delivery Conduct PK study for systemic exposure,Albuterol metered dose inhaler,Pharmacodynamics (PD) FDA Draft
11、 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 actin
12、g 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
13、 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,
14、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
15、 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,