Simulations Plus, Inc. · NASDAQ:SLP
Simulations Plus — Technical Presentation (2021)
21 slides from Simulations Plus's technical presentation, 2021
Slide 1: Pulmonary PBPK Modeling for Inhaled Products: Antibiotic Case Studies
GastroPlus® Pulmonary PBPK Modeling for Inhaled Products: Antibiotic Case Studies 2021 ISAM Congress James Mullin, Sr. Principal Scientist, Simulations Plus, Inc.
Slide 2: Pathways beyond oral absorption
Pathways beyond oral absorption… Ocular (OCAT™) Oral Cavity (OCCAT™) Pulmonary (PCAT™) Dermal (TCAT™) 2
Slide 3: What are we doing for inhaled products today?
What are we doing for inhaled products today? • Ability to assess exposure/concentration in any tissue • Assessment of therapeutic dose & dose range by linking simulated plasma or tissue concentrations to PD effect • Evaluation of formulation effects through Parameter Sensitivity Analysis Dosage f
Slide 4: Pulmonary Compartmental Absorption and Transit (PCAT) Model
Pulmonary Compartmental Absorption and Transit (PCAT™) Model (as implemented in GastroPlus® - developed in collaboration with GlaxoSmithKline) 1. Define API properties & 3. Predict local and systemic deposition fractions concentrations 2. Connect systemic PBPK model 4
Slide 5: Compartmentalization of the lung (ICRP66)
Compartmentalization of the lung (ICRP66) • ET1 = Anterior nasal passage • ET2 = Posterior nasal passage, oral cavity, larynx, pharynx, etc. • BB = Trachea and bronchi • Bb = Bronchioles (up to terminal) • AI = Respiratory bronchioles, alveolar duct, alveoli, etc. 5
Slide 6: Processes Involved in Nasal-Pulmonary Absorption
Processes Involved in Nasal-Pulmonary Absorption Passive and Blood Cpulmonary artery/ vein carrier mediated transport Lysosomal Tissue Ctissue Trapping Lymphatic Metabolism in Absorption the Tissue Cmucus Dissolution Mucociliary Mucociliary Transit In Drug in Transit Out solution, • dose or from • t
Slide 7: Compound Specific & Physiological Parameters
Compound Specific & Physiological Parameters Compound Specific Physiological Permeability in each tissue NEW! Lysosomal fractions Systemic absorption rate from NEW! Gas volumes nasal-pulmonary tissues Surface Area Enzyme and transport Mucus Layer Thickness parameters Tissue Volume
Slide 8: Regional Deposition Calculation
Regional Deposition Calculation Regional lung deposition can be predicted from particle size distribution or specified manually by the user Output (% deposited) that distributes the administered dose into different lung compartments Size distribution and additional information for drug carrier (exci
Slide 9: Capreomycin
Capreomycin Parameter Value Source logP -6.34 ADMET Predictor™ v7.2 pKa(s) 8.33 (Base); 11.35 (Acid) ADMET Predictor™ v7.2 Aqueous solubility 104 mg/mL @ pH 11 ADMET Predictor™ v7.2 GI permeability 0.0686 cm/s *10^-4 ADMET Predictor™ v7.2 Plasma protein binding 60% unbound Measured 1 Blood:plasma co
Slide 10: Modeling Objectives
Modeling Objectives • Develop a systemic PBPK model using available PK data following IV administration • Build a MAM/PBPK model for an OIDP at low dose • Validate the MAM/PBPK model for OIDPs at higher doses • Apply the MAM/PBPK model for an OIDP at highest dose to establish product specifications
Slide 11: Baseline Systemic PBPK Model Development
Baseline Systemic PBPK Model Development Model building steps: 1. Create virtual humans according to the subject demographics* 2. Define all tissues as permeability-limited models 3. Estimate tissue partitioning using published Poulin method (Poulin et al., 2002) 4. Calculate renal clearance as Fup
Slide 12: MAM/PBPK Model Building
MAM/PBPK Model Building Model building steps: 1. Define deposition fractions using in vitro data, MMAD, and ICRP method* 2. Calculate mucus membrane permeabilities using built-in GastroPlus PCAT™ approach 3. Optimize systemic absorption rate constants for lung compartment using low dose OIDP PK data
Slide 13: MAM/PBPK Model Validation
MAM/PBPK Model Validation OIDP 25 mg - Optimized OIDP 75 mg OIDP 150 mg OIDP 300 mg Observed (points) and simulated (lines) systemic PK profiles after 25 mg (A), 75 mg (B) , 150 mg (C), and 300 mg (D) inhaled administration of capreomycin*. The observed Cp-time profile after a 25 mg dose was used to
Slide 14: Particle Size Specifications: Sensitivity Analysis
Particle Size Specifications: Sensitivity Analysis Plasma Cmax [ng/mL] vs. Mass Median Aerodynamic Diameter [µm] Dose = 300 mg 2500 Simulated Plasma Cmax [ng/mL] 2000 1500 PSA can be used to establish particle size specifications. 1000 Results indicate that there would be small changes 500 (<20%) in
Slide 15: Particle Size Specifications: Local Exposure
Particle Size Specifications: Local Exposure Simulated Total Lung Concentration [µg/mL] vs. Time [hrs] Dose = 300 mg 180 Results indicate that there would be small changes (<20%) in local lung Simulated Total Lung Conc. [µg/mL] 160 MMAD = 2.84 um exposure over the first hour between 140 MMAD = 3.56
Slide 16: Dissolution or Deposition?
Particle Size Specifications: Dissolution or Deposition? Are MMAD changes on exposure driven by: Dissolution Rate? Deposition? 16
Slide 17: Sensitivity Analysis: Dissolution Rate
Sensitivity Analysis: Dissolution Rate Z-Factor Dissolution Model: 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 = 𝑍𝑍 𝐶𝐶𝑠𝑠 − 𝐶𝐶𝑙𝑙 ∗ 𝑀𝑀𝑢𝑢(𝑡𝑡) • Z represents z-factor (fitted to in vivo or in vitro dissolution data); • Cs is drug solubility; • Cl is local dissolved…
Slide 18: Validation Cases
Validation Cases PBPK models for deposition and disposition following inhaled & intranasal administration (Miller et al., RDD 2010) IVIVE for inhaled products (Salar-Behzadi et al., Int J Pharm 2017) Emerging technologies in inhaled Adult/pediatric PBPK models for product development pulmonary absor
Slide 19: Validation Cases
Validation Cases PBPK models for deposition and disposition following inhaled administration at different dose levels Machine learning+PBPK for (Mullin et al., RDD 2016) inhaled chemicals (Zhang et al., SAR QSAR Environ Res 2018) Risk assessment for DPI products (Radivojev et al., J Drug Del Sci PBP
Slide 20: Summary
Summary • MAM/PBPK model for capreomycin explains observed systemic PK for OIDPs across a dose range of 25 – 300 mg • Sensitivity analysis around MMAD helps establish particle size specifications based on local and systemic PK endpoints • MAM/PBPK model identifies that MMAD changes impact capreomyci
Slide 21: Questions & Answers
Questions & Answers SimulationsPlus simulations-plus.com/gastroplus