PK and PD Studies for Systemic Exposure of Locally Acting Drugs

Industry View

Lester I. Harrison, PhD

Division Scientist

3m Pharmaceuticals

Value of OINDP PK

• Systemic Absorption = Systemic Exposure

• Measure of systemic safety for locally acting drugs

• PK is an Established BE Metric– Standardized– Validated– Discriminating

OINDP PK Concerns

• Low Doses

• Assay LLOQ Limitations

• Variability

• Nose: Drainage of Excess Dose

• Oral Inhalation: Dosing Technique

OINDP PK Concern: Low Doses

• “Low” Dose Relative– Quantitatable

• Therapeutic Dose Range– More dose options

• Nasal Route– May be limited by drainage

OINDP PK Concern: Assay LLOQ

• LLOQ under 100 pg/mL common with LC/MS/MS

• Commercial Availability of Assays– Albuterol– BDP + Active Metabolite– Budesonide– Triamcinolone Acetonide– Cromolyn– Fluticasone Propionate?

OINDP PK Concern: Variability

• Large Inter-Subject Variability

• Large Intra-Subject Variability

• Dosing Technique

Nasal Formoterol VariabilityN = 27

Hochhaus et al, Pharmaceut Res 1992;9:291-297

Nasal Triamcinolone Acetonide Variability N = 12

Argenti et al, J Clin Pharmacol 1994;34:854-858

Nasal Budesonide Variability N = 16

Thorsson et al, Br J Clin Pharmacol 1999;47:619-624

Oral Inhalation Fluticasone Variability N = 12

Thorsson et al, Br J Clin Pharmacol 1997;43:155-161

Reducing Variability

• Replicate Study Designs

• Increased N

• Nasal - Reduce Dose

• Oral Inhalation - Inhalation Training– Not real world

BE Limitations of OINDP PK

• No Correlation with Efficacy– Corticosteroids

• Represents a Fraction of Dose– Usually Less Than 30%– Fine Particle Fraction?

• Summary Parameter of Absorption– Represents Mouth + GI + First Pass + Lungs– Different Rates and Extents of Absorption

Nasal Fluticasone PK & EfficacyN = 280

DoseDay 15

SymptomScore

C1

pg/mL

Nasal200 mcg/dy

133 BKGD

Oral5 mg/dy

212 103

Oral10 mg/dy

194 137

Placebo 217 BKGD

Howland et al, Clin Therap 1996;18:1106-1117

Oral Inhaled Fluticasone PK & EfficacyN = 261

DoseWeek 6

AM FEV1

Change, LSymptomScore

Cmaxpg/mL

AUCpg/h/mL

Inhaled200 mcg/dy

0.27 -0.17 BLQ BLQ

Inhaled1000 mcg/dy

0.42 -0.22 116 629

Oral20 mg/dy

-0.2 0.04 248 1230

Placebo -0.19 0.06 BLQ BLQ

Lawrence et al, Am J Respir Crit Care Med 1997;156:744-751

Value of OINDP PK: Conclusions

• PK Useful to Establish Systemic Absorption

• Not a Surrogate for Local Efficacy

• Doable

• Can Reduce Variability

• Systemic BE?

BDP MDI Examples Systemic Absorption Studies

• Formulations: MDI A vs. MDI B

• Study Designs– Single Dose (multiple inhalations)– Asthmatics– Crossover– Good Inhalation Technique

BDP Comparative Absorption StudiesMDI A vs. MDI B

• Q1 …….. ……………… same

• Q2 ………………………… same

• Particle Size Dist ……… essentially same

• Spray Pattern …………… essentially same

• Valve Size …..………… same

• Actuator Dimensions…… essentially same

Oral Inhaled BDP PK Study 1

• Objective: Systemic Comparability

• N = 18 Asthmatics

• Cmax: CI = 0.79 - 1.12; CV = 51%

• AUC: CI = 0.90 - 1.35; CV = 42%

Oral Inhaled BDP PK Study 2

• Objective: Systemic BE

• N = 45 Asthmatics

• CmaxL: CI = 0.85 - 1.01; CV = 30%

• CmaxH: CI = 0.80 - 0.95; CV = 49%

• AUCL; CI = 0.85 - 0.95; CV = 23%

• AUCH; CI = 0.86 - 0.97; CV = 22%

Concluded Systemic Equivalence Ran Local Delivery Study for Efficacy

BDP MDI Examples Systemic Absorption Studies

• Formulations: MDI C vs. MDI D– Different Strengths– Same Dose, Different Number of Puffs

• Study Designs– Single Dose (multiple inhalations)– Asthmatics– Crossover– Good Inhalation Technique

BDP Comparative Absorption StudiesMDI C vs. MDI D

• Q1 …….. ……………… same

• Q2 ………………………… same

• Particle Size Dist ……… same

• Spray Pattern …………… same

• Valve Size …..………… different

• Actuator Dimensions……same

Oral Inhaled BDP PK Study 3

• Objective: Systemic Comparability

• N = 18 Asthmatics

• Cmax: CI = 0.76 - 1.00; CV = 32%

• AUC; CI = 0.86 - 1.19; CV = 37%

Oral Inhaled BDP PK Study 4

• Objective: Systemic BE• N = 30 Asthmatics

• CmaxL: CI = 0.82 - 1.11; CV = 46%

• CmaxH: CI = 0.81 - 1.11; CV = 34%

• AUCH; CI = 0.81 - 1.22; CV = 37%

Concluded Systemic Equivalence Ran Local Delivery Studies on Each MDI

PK Options: Charcoal Block

• Allows Differentiation of Pulmonary and Non-Pulmonary Absorbed Drug

• Utilizes Same Drug Assays and Metrics – Little additional time or cost

• Do Not Have to Alter Reference or Test Products

BE Limitations of Charcoal Block

• No Evidence that Pulmonary Absorbed Drug Correlates with Efficacy

• Does Not Discriminate Potentially Important Product Differences– Oropharayngeal Deposition– Regional Lung Deposition

Very Useful Laboratory Tool– “Pulmonary” Drug Absorption– Potential Surrogate for Local Delivery?

PK Options: Urinary Excretion

• When PK Not Doable

• Reported for– Albuterol– Cromolyn– Nedocromil– Ipratropium

Nasal Ipratropium BromideN = 22

• 24-Hour Urinary Excretion

10.6 1.9 g (mean SE)

CV = 84%

• Percent Dose Excreted

6.3 1.2%

CV = 89%

Wood et al, J Allergy Clin Immunol 1995;95:1111-1116

BE Limitations of Urinary Excretion

• High Variability

• Low Sensitivity

Unlikely to be a Reliable Surrogate

PK Options: PD Measurement

• When PK Not Doable

• Requires Appropriate Study Design– Dose Response Curve– Repeat Administration

BE Limitations of PD

• High Variability

• Low Sensitivity

• Requires Multiple Dose Levels

Difficult Task if PK Not Doable

PK Options: PK-PD

• Allows Correlation of PK with PD– PK Linear– PD Dose Response Curve

• Increased Understanding – Systemic Exposure– Systemic Safety

BE Limitations of PK-PD

• Requires Several Dose Levels, Additional Analyses

• Does Not Increase Ability to Differentiate Products

• Very Useful Laboratory Tool

Development Technique

SUMMARY

• Systemic PK Assessment – Needed to Assure Systemic Safety– Doable for Most Drugs

• PD, Urine Levels – Not Likely Surrogates

• Charcoal Block, PK-PD– Development Tools

FDA Question: Are There Situations Where In Vitro Data + PK + PD Can Be Relied on to Assure Local Efficacy

• Can Be Relied On To Assure Implies Predictability– Beta-Agonists– Corticosteroids– Cromolyn– Anticholinergics– Antihistamines

• Solutions? Need for Caution Until Predictability

Demonstrated