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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-IIOffice of Clinical Pharmacology&BiopharmaceuticsCenter for Drug Evaluation&Research,FDA,Outline,Why oral inhalation and nasal deliveryWh
2、y pharmacokinetics(PK)Examples of locally acting drug productsExamples of systemically acting drug productsDifficulties with PK for nasal&inhalation productsSummary,Why nasal and oral inhalation delivery,LOCAL ACTION:Alternate route of administration of drugsIntention is to minimize systemic exposur
3、eGenerally faster onset of actionConvenienceSYSTEMIC ACTION:Rapid absorption,higher bioavailability-Lower dose neededAvoidance of metabolism&irritation in GITGenerally faster onset of actionConvenience,Approaches to establish bioavailability/bioequivalence,21 CFR 320.24:In descending order of accura
4、cy,sensitivity and reproducibility:Pharmacokinetic studiesPharmacodynamic studiesWell-controlled clinical trialsIn vitro testsAny other approach deemed adequate by FDA,Pharmacokinetics,Pharmacodynamics,Clinical efficacy/safety,In vitro,Why not BA/BE based on PK alone,Systemic exposure data represent
5、s safety for locally acting drug productsTo address efficacy issues-also need clinical data,Fate of inhaled drug products,Amount reaching systemic circulation=pulmonary+oral(GI)BA fractionsRef:American J.Of Respiratory&Critical Care Medicine,03/98,vol.157,3(2),7-244,Inhalation PK with charcoal block
6、,Administration of activated charcoal with some inhaled drugs can block the absorption from GITSystemic drug concentrations with charcoal block represent absorption via respiratory tractUseful in comparing relative dose delivery to lung from different formulationsDoes not address Regional lung depos
7、ition Oropharyngeal deposition,Lung deposition-Gamma scintigraphy,Drug delivery to a local site assessed via in vivo imaging99m Technetium used as a radiolabelSome current concernsLabeled drug may have altered aerodynamicsSignal attenuation due to body tissueUnclear definition of clinically relevant
8、 biospacePossible lab-to-lab variation,Nasal Guidance,Guidance for Industry:Bioavailability&Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local ActionBA&BE-Product quality Nasal solution products-In vitro data onlyNasal suspension productsIn vitro dataClinical studies for local deli
9、verySystemic absorption studiesPharmacokineticsPharmacodynamics BA-PK/PD/Clinical,Decision tree for in vivo product quality BA/BE studies for nasal products,Is the formulationa suspension?,No in vivo studies forsolution formulations,Conduct clinical study forlocal deliveryConduct PD/clinical studyfo
10、r systemic absorption,Is a PK studyfeasible?,NO,NO,YES,YES,Conduct clinical study forlocal deliveryConduct PK study forsystemic exposure,Albuterol metered dose inhaler,Pharmacodynamics(PD)FDA Draft Guidance,Nasal Guidance-PK recommendations,PK study for systemic exposureSingle or multiple doseNonrep
11、licate or replicate designHealthy subjects or patientsNumber of doses may exceed labeled dose(loss of drug should be minimized)*Additional pilot study recommended,Examples of locally acting nasal products,Examples of systemically acting nasal products,Study designs used in these examples,CrossoverPa
12、rallelDifferent dose levelsSingle dose&/or multiple dose,PK studies:Issues,Low doseAssay sensitivityVariabilityLimitations of volume/dose:25 to 200 mL-excess volume may lead to drainage to outside or to oropharyngeal region,PK studies:Feasibility,Several antihistaminesSystemically acting drugsSome s
13、teroids,Examples of oral inhalation products,Study designs used in these examples,CrossoverParallelDifferent dose levelsSingle dose&/or multiple dose,PK studies:Issues,Low doseAssay sensitivityVariabilityFeasibility of administering multiple puffs/dose,PK studies:Feasibility,Some beta agonistsMost c
14、orticosteroidsSystemically acting drugs,SYSTEMIC ABSORPTION WITH PK,PHARMACODYNAMICS,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,
