1. PK and PD Studies for Systemic Exposure of Locally Acting Drugs Industry View Lester I. Harrison, PhD Division Scientist 3m Pharmaceuticals

2. 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

3. OINDP PK Concerns Low Doses Assay LLOQ Limitations Variability Nose: Drainage of Excess Dose Oral Inhalation: Dosing Technique

4. OINDP PK Concern: Low Doses “Low” Dose Relative –Quantitatable Therapeutic Dose Range –More dose options Nasal Route –May be limited by drainage

5. 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?

6. OINDP PK Concern: Variability Large Inter-Subject Variability Large Intra-Subject Variability Dosing Technique

7. Nasal Formoterol Variability N = 27 Hochhaus et al, Pharmaceut Res 1992;9:291-297

8. Nasal Triamcinolone Acetonide Variability N = 12 Argenti et al, J Clin Pharmacol 1994;34:854-858

9. Nasal Budesonide Variability N = 16 Thorsson et al, Br J Clin Pharmacol 1999;47:619-624

10. Oral Inhalation Fluticasone Variability N = 12 Thorsson et al, Br J Clin Pharmacol 1997;43:155-161

11. Reducing Variability Replicate Study Designs Increased N Nasal - Reduce Dose Oral Inhalation - Inhalation Training –Not real world

12. 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

13. Nasal Fluticasone PK & Efficacy N = 280 Howland et al, Clin Therap 1996;18:1106-1117

14. Oral Inhaled Fluticasone PK & Efficacy N = 261 Lawrence et al, Am J Respir Crit Care Med 1997;156:744-751

15. Value of OINDP PK: Conclusions PK Useful to Establish Systemic Absorption Not a Surrogate for Local Efficacy Doable Can Reduce Variability Systemic BE?

16. BDP MDI Examples Systemic Absorption Studies Formulations: MDI A vs. MDI B Study Designs –Single Dose (multiple inhalations) –Asthmatics –Crossover –Good Inhalation Technique

17. BDP Comparative Absorption Studies MDI A vs. MDI B Q1 …….. ……………… same Q2 ………………………… same Particle Size Dist ……… essentially same Spray Pattern …………… essentially same Valve Size …..………… same Actuator Dimensions…… essentially same

18. 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%

19. Oral Inhaled BDP PK Study 2 Objective: Systemic BE N = 45 Asthmatics Cmax L : CI = 0.85 - 1.01; CV = 30% Cmax H : CI = 0.80 - 0.95; CV = 49% AUC L ; CI = 0.85 - 0.95; CV = 23% AUC H ; CI = 0.86 - 0.97; CV = 22%  Concluded Systemic Equivalence  Ran Local Delivery Study for Efficacy

20. 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

21. BDP Comparative Absorption Studies MDI C vs. MDI D Q1 …….. ……………… same Q2 ………………………… same Particle Size Dist ……… same Spray Pattern …………… same Valve Size …..………… different Actuator Dimensions……same

22. 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%

23. Oral Inhaled BDP PK Study 4 Objective: Systemic BE N = 30 Asthmatics Cmax L : CI = 0.82 - 1.11; CV = 46% Cmax H : CI = 0.81 - 1.11; CV = 34% AUC H ; CI = 0.81 - 1.22; CV = 37%  Concluded Systemic Equivalence  Ran Local Delivery Studies on Each MDI

24. 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

25. 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?

26. PK Options: Urinary Excretion When PK Not Doable Reported for –Albuterol –Cromolyn –Nedocromil –Ipratropium

27. Nasal Ipratropium Bromide N = 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

28. BE Limitations of Urinary Excretion High Variability Low Sensitivity  Unlikely to be a Reliable Surrogate

29. PK Options: PD Measurement When PK Not Doable Requires Appropriate Study Design –Dose Response Curve –Repeat Administration

30. BE Limitations of PD High Variability Low Sensitivity Requires Multiple Dose Levels  Difficult Task if PK Not Doable

31. PK Options: PK-PD Allows Correlation of PK with PD –PK Linear –PD Dose Response Curve Increased Understanding –Systemic Exposure –Systemic Safety

32. BE Limitations of PK-PD Requires Several Dose Levels, Additional Analyses Does Not Increase Ability to Differentiate Products Very Useful Laboratory Tool  Development Technique

33. 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

34. 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