10 April 2019 10 Biopharmaceutical Classification of Inhaled Medicines: Development of an iBCS Jayne E Hastedt, PhD 1 Co-Chair of PQRI BTC iBCS Working Group 4th FDA/PQRI4th Conference Outline April 2019 10 m The Oral BCS (giBCS) m Developing a Classification System for Inhaled Medicines m Determining the Classification Parameters m Generating iBCS Classification Grids and Modelling 2 m Summary and Next Steps 4th FDA/PQRI4th Conference What is the BCS? April 2019 10 m The Biopharmaceutics Classification System (oral BCS or giBCS), is a science-based classification system used and developed for orally administered, immediate release drugs. m The giBCS uses three simple, derived dimensionless numbers that take into account the dissolution, dose, and absorption for a particular drug 3 substance. m The giBCS is focused on oral drugs with systemic activity. m Using the dose number, dissolution number, and absorption number, one can classify drugs based on solubility and permeability. Amidon, G. L.; Lennernas, H.; Shah, V. P.; Crison, J. R. A Theoretical Basis for a Biopharmaceutical Drug Classification: The Correlation of in vitro Drug Product Dissolution and in vivo Bioavailability. Pharm. Res. 1995, 12: 413-420 4th FDA/PQRI4th Conference BCS For Orally Administered Drugs (giBCS) April 2019 10 Benefits: • Drug discovery/design • Screening techniques • Formulation strategies • Addressing the “lows” 4 • Biowaivers • BCS Class I • BCS Class III • IVIVC Potential • BCS Class II • BCS Class I FDA. Guidance for Industry Guidance for Industry Waiver of In Vivo BioavaiLabiLity and BioequivaLence Studies for IR SoLid Oral Dosage Forms Based on BCS; 2015. Amidon, G. L.; Lennernas, H.; Shah, V. P.; Crison, J. R. Pharm. Res. 1995, 12, 413–420. FDA/PQRI4th Conference 10 April 2019 10 Can a BCS-like classification system be developed for inhaled medicines? 5 ? = 4th FDA/PQRI4th Conference Developing a Classification System for Inhaled Medicines m Goal: April 2019 10 m Develop a physiologically-based pulmonary drug product classification system based on biorelevant drug and product attributes. m Scope: m The classification system will be based on scientific principles, current understanding of pulmonary physiology, and relevant phys chem properties. 6 m Initial focus will be on locally acting therapeutics and will exclude antibiotics, systemic delivery, metabolized drugs (pro-drugs), and protein therapeutics. m Initial drug and product attributes to be evaluated: msolubility and dissolution rate mdose and deposition mabsorption and disposition. 4th FDA/PQRI4th Conference Developing an iBCS for Inhaled Medicines – Value and Challenges m Value: April 2019 10 m Generate a common set of tools to aide pulmonary drug product development efforts. m De-risk the development of inhaled medicines. m Support bioequivalence assessment and generic product approvals for pulmonary drug products. m Challenges: 7 m Inability to measure local drug concentrations in vivo. m Limited data sets – the number of inhaled medicines is small compared to oral medicines and complete data sets are often not published. m A complete list of harmonized biorelevant testing and characterization techniques are lacking for pulmonary drugs. m Simulation approaches are still under development and any model will require validation. 4th FDA/PQRI4th Conference Developing a Biopharmaceutics Classification System is an Iterative Process April 2019 10 Understand physiology of the target organ Validate and Collect confirm the relevant classification biopharm 8 system/ properties of approach drugs Identify the Construct critical quality grid(s) and and determine performance boundaries attributes 4th FDA/PQRI4th Conference 10 April 2019 10 Determining the Drug and Product Classification Parameters Start with the giBCS parameters and modify based on lung physiology and product understanding 9 4th FDA/PQRI4th Conference Properties of The Tube (Oral GI) and the Tube + Bucket (Lung) 10 April 2019 10 Property GI Lung Description “Tube” “Tube + Bucket” Typical site of action Systemic Local Transit or Residence 199 minutes 1 – 24 hours time (mean intestinal transit time) 50 – 1,100 mL 15 – 70 mL “Fluid” volume Average: 500 mL 10 Surface fluid layers with Bulk liquid location-specific viscosity, “Fluid” properties Location-specific pH composition and thickness Range: 1.4 – 7.4 Stomach: 1.4 – 2.1 6.69 ± 0.07 pH Range* Duodenum: 4.4 – 6.6 (~5 in macrophages) Ileum: 6.5 – 7.4 Dose mcg – 1000mg 10 mcg – 50 mg *fasted state Adapted from Hastedt, J. E. Inhalation Magazine. 2014, pp. 18–22. Rennard, S.I. et al., Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution”, J. Appl. Physiology, 60, 532-538. Effros, R. M., and F. P. Chinard*Fasted. 1969. state“The infor Vivo oral PH route. of the Extravascular Space of the Lung.” Journal of Clinical Investigation 48: 1983–96. doi:10.1172/JCI106164. FDA/PQRI4th Conference The Lung Anatomy – approximate ranges – everyone is different! 10 April 2019 10 Conducting (Central) Zone Respiratory (Peripheral) Zone • Trachea • Respiratory Bronchioles • Bronchi • Alveolar Ducts • Bronchioles • Alveoli • Terminal Bronchioles • Volume: ~5,000 cm3 3 2 Gray’s Anatomy, 1918. • Volume: ~175 cm • Surface Area: ~60 – 140 m • Surface Area: ~1-2.5 m2 11 Key Learning: - The surface area of the peripheral airways >> than the central airways These values are estimates based on various references/authors. Diseased lungs are different Mercer, R.R., Russell, M.L., Roggli,V.L. and Crapo, J.D. (1994) Cell number and distribution in human and rat airways. Am. J. Respir. Cell Mol. Biol. 10, 613-624. Weibel, E.R. (1973) Morphological basis of alveolar- capillary gas exchange. Physiol. Rev. 53, 419-495. Thurlbeck. W.M. (1967) The internal surface area of nonemphysematous lungs. Am. Rev. Respir. Dis. 95, 765-770. Stone, K.C., Mercer, R.R., Gehr, P., Stockstill, B. and Crapo, J.D. (1992) Allometric relationships of cell numbers and size in the mammalian lung. Am. Respir. Cell Mol. Biol. 6, 235-243. FDA/PQRI4th Conference The Lung Anatomy by Region 10 April 2019 10 The upper airways (conducting zone) are covered with a non-Newtonian layer of mucus – thickness varies by location. • The upper airways are ciliated. The lower airways (alveoli/respiratory zone) are covered with a thin layer of Newtonian 12 lung surfactant-rich film. Key Learnings: - Clearance mechanisms vary by region. - “Liquid” composition and thickness vary by region. Patton, J. S.; Byron, P. R. Inhaling medicines: delivering drugs to the body through the lungs. Nat. Rev. Drug Discov. 2007, 6, 67–74. Wang, Y.-B.; Watts, A. B.; Peters, J. I.; Williams, R. O. The impact of pulmonary diseases on the fate of inhaled medicines--a review. Int. J. Pharm. 2014, 461, 112–28. 4th FDA/PQRI4th Conference The iBCS Development Process 10 April 2019 10 m Development of a pulmonary drug product classification system will be based on critical attributes for pulmonary drugs and drug products. m Critical attributes for pulmonary drugs: mDose and deposition mPermeability and tissue interaction (disposition) mDissolution and solubility mGeneral phys chem properties (diffusion, charge, partition coef, etc.) 13 m Classify measurable attributes onto grid(s) m Use PBPK and compartmental PK models to confirm classification (sensitivity) and application (validation) through simulation studies. m Outcomes: m Identify attribute “Rule of Thumb” assumptions and a classification grid with defined boundaries. m Identify modeling tools for BE assessment. 4th FDA/PQRI4th Conference The iBCS Process Map Physical and April 2019 10 Biopharmaceutical Industry data Attributes – identification and PK model validation PK/Molecule range-finding properties Deposition and Dose Modeling studies 14 Physicochemical Input properties – including Modelling solubility and sensitivities dissolution Biological attributes – Output permeability and disposition Confirmation Reality and Define an iBCS pressure checks 4th FDA/PQRI4th Conference Potential Classification Grids for Inhaled Medicines Inhaled for Grids Classification Potential Pulmonary physiology + Biopharmaceutics + CQAs 4th FDA/PQRI Conference 15 10 April 2019 Fundamental iBCS Operating Assumptions April 2019 10 m For any given drug: m The regional dose and deposition pattern, dissolution rate, and tissue interactions (including permeability) will dictate the local concentration and retention time within the lung. m In the case when two drug products contain the same drug and excipients: 16 m Identical regional dose deposition patterns and dissolution rates will ensure the same local concentrations within the lung. 4th FDA/PQRI4th Conference Developing the iBCS Grids – Further Assumptions m Parameters: April 2019 10 m Solubility/dissolution rate and permeability/retention time are the key properties impacting local drug concentrations and systemic exposure. m Deposition/Dose and Clearance: m Deposited dose: 50% central and 50% peripheral of lung dose m Dissolved drug is not cleared by MCC; clearance by absorption only in peripheral airways 17 m Retention Time: m Since we cannot measure local drug concentrations and regional binding/transport, we can use MAT (Mean Absorption Time) to describe retention of drug in the lung. m Since the central and peripheral regions of the lung have different physiological properties, we will need 2 regional classification grids (as a start). 4th FDA/PQRI4th Conference A Conceptual Biopharmaceutics Diagram for the Lung 10 April 2019 10 Low solubility/