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PK and PD Studies for Systemic Exposure of Locally Acting Drugs Industry View

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

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PK and PD Studies for Systemic Exposure of Locally Acting Drugs Industry View

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  1. PK and PD Studies for Systemic Exposure of Locally Acting DrugsIndustry 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 VariabilityN = 27 Hochhaus et al, Pharmaceut Res 1992;9:291-297

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

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

  10. Oral Inhalation Fluticasone VariabilityN = 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 & EfficacyN = 280 Howland et al, Clin Therap 1996;18:1106-1117

  14. Oral Inhaled Fluticasone PK & EfficacyN = 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 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

  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 • 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

  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 StudiesMDI 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 • 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

  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 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

  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

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