1、pharmacokinetic testing for systemic exposure of orally inhaled and nasal drugsvenkata ramana s. uppoor, m.pharm., ph.d., r.ph.division of pharmaceutical evaluation - iioffice of clinical pharmacology & biopharmaceuticscenter for drug evaluation & research, fdaoutlinewhy oral inhalation and nasal de

2、liverywhy pharmacokinetics (pk)examples of locally acting drug productsexamples of systemically acting drug productsdifficulties with pk for nasal & inhalation productssummarywhy nasal and oral inhalation deliverylocal action:alternate route of administration of drugsintention is to minimize systemi

3、c exposuregenerally faster onset of actionconveniencesystemic action:rapid absorption, higher bioavailability - lower dose neededavoidance of metabolism & irritation in gitgenerally faster onset of actionconvenienceapproaches to establish bioavailability/bioequivalence21 cfr 320.24: in descending or

4、der of accuracy, sensitivity and reproducibility:pharmacokinetic studiespharmacodynamic studieswell-controlled clinical trialsin vitro testsany other approach deemed adequate by fdawhy not ba/be based on pk alonesystemic exposure data represents safety for locally acting drug productsto address effi

5、cacy issues - also need clinical datafate of inhaled drug productsinhalation pk with charcoal blockadministration of activated charcoal with some inhaled drugs can block the absorption from gitsystemic drug concentrations with charcoal block represent absorption via respiratory tractuseful in compar

6、ing relative dose delivery to lung from different formulationsdoes not address regional lung deposition oropharyngeal depositionlung deposition - gamma scintigraphydrug delivery to a local site assessed via in vivo imaging99m technetium used as a radiolabelsome current concernslabeled drug may have

7、altered aerodynamicssignal attenuation due to body tissueunclear definition of clinically relevant biospacepossible lab-to-lab variationnasal guidance nasal solution products - in vitro data onlynasal suspension productskin vitro datakclinical studies for local deliveryksystemic absorption studieslp

8、harmacokineticslpharmacodynamics decision tree for in vivo product quality ba/be studies for nasal productsalbuterol metered dose inhalerpharmacodynamics (pd)fda draft guidancenasal guidance - pk recommendationspk study for systemic exposuresingle or multiple dosenonreplicate or replicate designheal

9、thy subjects or patientsnumber of doses may exceed labeled dose (loss of drug should be minimized)* additional pilot study recommendedexamples of locally acting nasal productsdrugsmeasurable at recommended doses?fluticasonenotriamcinoloneyesbudesonidenomometasonenoazelastineyeslevocabastineyes (lite

10、rature)examples of systemically acting nasal productsdrugsmeasurable at recommended doses?sumatriptanyesbutorphanolyesstudy designs used in these examples zcrossoverzparallelzdifferent dose levelszsingle dose &/or multiple dosepk studies: issueslow doseassay sensitivityvariabilitylimitations of volu

11、me/dose : 25 to 200 ml - excess volume may lead to drainage to outside or to oropharyngeal regionpk studies: feasibilityseveral antihistaminessystemically acting drugssome steroidsexamples of oral inhalation productsdrugsmeasurable at recommended doses?fluticasoneyestriamcinoloneyes (?)budesonideyes

12、albuterolnosalmeterolnoinsulin (systemic)yes (literature)study designs used in these examples zcrossoverzparallelzdifferent dose levelszsingle dose &/or multiple dosepk studies: issueslow doseassay sensitivityvariabilityfeasibility of administering multiple puffs/dosepk studies: feasibilitysome beta agonistsmost corticosteroidssystemically acting drugssummarypharmacokinetic studies are the first choice to characterize systemic exposure of nasal and oral inhalation products. however, difficulties may be encountered in using pk for doc