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, Venkata Ramana S. Uppoor, M.Pharm., Ph.D., R.Ph.M.Pharm., Ph.D., R.Ph.

Division of Pharmaceutical Evaluation - IIDivision of Pharmaceutical Evaluation - II

Office of Clinical Pharmacology & BiopharmaceuticsOffice of Clinical Pharmacology & Biopharmaceutics

Center for Drug Evaluation & Research, FDACenter for Drug Evaluation & Research, FDA

OutlineOutline

Why oral inhalation and nasal deliveryWhy oral inhalation and nasal delivery Why pharmacokinetics (PK)Why pharmacokinetics (PK) Examples of locally acting drug productsExamples of locally acting drug products Examples of systemically acting drug productsExamples of systemically acting drug products Difficulties with PK for nasal & inhalation Difficulties with PK for nasal & inhalation

productsproducts SummarySummary

Why nasal and oral inhalation deliveryWhy nasal and oral inhalation delivery

LOCAL ACTION:LOCAL ACTION: Alternate route of administration of drugsAlternate route of administration of drugs Intention is to minimize systemic exposureIntention is to minimize systemic exposure Generally faster onset of actionGenerally faster onset of action ConvenienceConvenience

SYSTEMIC ACTION:SYSTEMIC ACTION: Rapid absorption, higher bioavailability - Lower dose neededRapid absorption, higher bioavailability - Lower dose needed Avoidance of metabolism & irritation in GITAvoidance of metabolism & irritation in GIT Generally faster onset of actionGenerally faster onset of action ConvenienceConvenience

Approaches to establish bioavailability/bioequivalenceApproaches to establish bioavailability/bioequivalence

21 CFR 320.2421 CFR 320.24: In descending order of : In descending order of accuracy, sensitivity and reproducibility:accuracy, sensitivity and reproducibility:

Pharmacokinetic studiesPharmacokinetic studies Pharmacodynamic studiesPharmacodynamic studies Well-controlled clinical trialsWell-controlled clinical trials In vitro testsIn vitro tests Any other approach deemed adequate by FDAAny other approach deemed adequate by FDA

PharmacokineticsPharmacokinetics

PharmacodynamicsPharmacodynamics

Clinical efficacy/safetyClinical efficacy/safety

In vitroIn vitro

Why not BA/BE based on PK aloneWhy not BA/BE based on PK alone

Systemic exposure data represents Systemic exposure data represents safety for locally acting drug productssafety for locally acting drug products

To address efficacy issues - also need To address efficacy issues - also need clinical dataclinical data

Fate of inhaled drug productsFate of inhaled drug products

Amount reaching systemic circulation = pulmonary + oral (GI) BA fractionsAmount reaching systemic circulation = pulmonary + oral (GI) BA fractionsRef: American J. Of Respiratory & Critical Care Medicine, 03/98, vol. 157, 3 (2), 7-244Ref: American J. Of Respiratory & Critical Care Medicine, 03/98, vol. 157, 3 (2), 7-244

Inhalation PK with charcoal blockInhalation PK with charcoal block

Administration of activated charcoal with some inhaled Administration of activated charcoal with some inhaled drugs can block the absorption from GITdrugs can block the absorption from GIT

Systemic drug concentrations with charcoal block represent Systemic drug concentrations with charcoal block represent absorption via respiratory tractabsorption via respiratory tract

Useful in comparing relative dose delivery to lung from Useful in comparing relative dose delivery to lung from different formulationsdifferent formulations

Does not address Does not address Regional lung deposition Regional lung deposition Oropharyngeal depositionOropharyngeal deposition

Lung deposition - Gamma scintigraphyLung deposition - Gamma scintigraphy

Drug delivery to a local site assessed via in vivo Drug delivery to a local site assessed via in vivo imagingimaging

99m99m Technetium used as a radiolabel Technetium used as a radiolabel Some current concernsSome current concerns

Labeled drug may have altered aerodynamicsLabeled drug may have altered aerodynamics Signal attenuation due to body tissueSignal attenuation due to body tissue Unclear definition of clinically relevant biospaceUnclear definition of clinically relevant biospace Possible lab-to-lab variationPossible lab-to-lab variation

Nasal GuidanceNasal Guidance

Guidance for Industry: Bioavailability & Bioequivalence Studies for Nasal Guidance for Industry: Bioavailability & Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local ActionAerosols and Nasal Sprays for Local Action

BA & BE - Product qualityBA & BE - Product quality Nasal solution products - In vitro data onlyNasal solution products - In vitro data only Nasal suspension productsNasal suspension products

In vitro dataIn vitro data Clinical studies for local deliveryClinical studies for local delivery Systemic absorption studiesSystemic absorption studies

PharmacokineticsPharmacokinetics PharmacodynamicsPharmacodynamics

BA - PK/PD/ClinicalBA - PK/PD/Clinical

Decision tree for in vivo product quality BA/BE studies for nasal productsDecision tree for in vivo product quality BA/BE studies for nasal products

Is the formulationIs the formulationa suspension?a suspension?

No in vivo studies forNo in vivo studies forsolution formulationssolution formulations

Conduct clinical study forConduct clinical study forlocal deliverylocal delivery

Conduct PD/clinical studyConduct PD/clinical studyfor systemic absorptionfor systemic absorption

Is a PK studyIs a PK studyfeasible?feasible?

NONO

NONOYESYES

YESYES

Conduct clinical study forConduct clinical study forlocal deliverylocal delivery

Conduct PK study forConduct PK study forsystemic exposuresystemic exposure

Albuterol metered dose inhalerAlbuterol metered dose inhaler

Pharmacodynamics (PD)Pharmacodynamics (PD)FDA Draft GuidanceFDA Draft Guidance

Nasal Guidance - PK recommendationsNasal Guidance - PK recommendations

PK study for systemic exposurePK study for systemic exposure Single or multiple doseSingle or multiple dose Nonreplicate or replicate designNonreplicate or replicate design Healthy subjects or patientsHealthy subjects or patients Number of doses may exceed labeled dose (loss Number of doses may exceed labeled dose (loss

of drug should be minimized)of drug should be minimized)

* Additional pilot study recommended* Additional pilot study recommended

Examples of locally acting nasal productsExamples of locally acting nasal products

Drugs Measurable at recommended doses?

Fluticasone NoTriamcinolone YesBudesonide NoMometasone NoAzelastine YesLevocabastine Yes (literature)

Examples of systemically acting nasal productsExamples of systemically acting nasal products

Drugs Measurable at recommended doses?

Sumatriptan YesButorphanol Yes

Study designs used in these examples Study designs used in these examples

CrossoverCrossover ParallelParallel Different dose levelsDifferent dose levels Single dose &/or multiple doseSingle dose &/or multiple dose

PK studies: IssuesPK studies: Issues

Low doseLow doseAssay sensitivityAssay sensitivityVariabilityVariabilityLimitations of volume/dose : 25 to 200 Limitations of volume/dose : 25 to 200 L L

- excess volume may lead to drainage to - excess volume may lead to drainage to outside or to oropharyngeal regionoutside or to oropharyngeal region

PK studies: FeasibilityPK studies: Feasibility

Several antihistaminesSeveral antihistaminesSystemically acting drugsSystemically acting drugsSome steroidsSome steroids

Examples of oral inhalation productsExamples of oral inhalation products

Drugs Measurable at recommended doses?

Fluticasone YesTriamcinolone Yes (?)Budesonide YesAlbuterol NoSalmeterol NoInsulin (systemic) Yes (literature)

Study designs used in these examples Study designs used in these examples

CrossoverCrossover ParallelParallel Different dose levelsDifferent dose levels Single dose &/or multiple doseSingle dose &/or multiple dose

PK studies: IssuesPK studies: Issues

Low doseLow doseAssay sensitivityAssay sensitivityVariabilityVariabilityFeasibility of administering multiple Feasibility of administering multiple

puffs/dosepuffs/dose

PK studies: FeasibilityPK studies: Feasibility

Some beta agonistsSome beta agonistsMost corticosteroidsMost corticosteroidsSystemically acting drugsSystemically acting drugs

SYSTEMIC ABSORPTION WITH PKSYSTEMIC ABSORPTION WITH PK

PHARMACODYNAMICSPHARMACODYNAMICS

SummarySummary

Pharmacokinetic studies are the first choice to Pharmacokinetic studies are the first choice to characterize systemic exposure of nasal and oral characterize systemic exposure of nasal and oral inhalation products. However, difficulties may inhalation products. However, difficulties may be encountered in using PK for documentation of be encountered in using PK for documentation of bioavailability/bioequivalence for some locally bioavailability/bioequivalence for some locally acting nasal and oral inhalation drug products. In acting nasal and oral inhalation drug products. In those cases, pharmacodynamic data need to be those cases, pharmacodynamic data need to be used to characterize the systemic absorptionused to characterize the systemic absorption