Simulations Plus, Inc. · NASDAQ:SLP
Simulations Plus — Technical Presentation (December 2020)
52 slides from Simulations Plus's technical presentation, Dec 11, 2020
Slide 1: GastroPlus applications to various drug delivery routes of administration
G a st ro P| us aapS-VCU Student Chapter GastroPlus applications to various drug delivery routes of administration Webinar: Friday, December 11 7:30 PM CET (Paris) / 10:30 AM PDT (Los Angeles) / 1:30 PM EDT (New York) https://zoom.us/join John DiBella Meeting ID: 986 1112 0237 Maxime Le Merdy Passco
Slide 2: Outline
Outline Locally acting drug products • Ophthalmic route of administration • Inhalation route of administration Pharmacodynamic modeling with GastroPlus 2
Slide 3: Locally acting drug products
Locally acting drug products 3
Slide 4: Locally-Acting Drugs?
Locally-Acting Drugs? • The main site of action is local, e.g. the skin, the mucosal surface of the nose or lungs, the eyes, the gastrointestinal tract… • Drug products not intended to be absorbed into the bloodstream • If the API is detectable in plasma, does the plasma concentration time course re
Slide 5: Evaluation of BE for Topical Products
Evaluation of BE for Topical Products ¢ A Modular Framework for Characterization-Based BE * Qualitative (Q1) and Quantitative (Q2) Sameness or ‘No Difference’ ¢ Physical and Structural (Q3) Sameness or ‘Similarity’ * IVRT (In Vitro Release Test) ¢ IVPT (In Vitro Permeation Test) ¢ Other Types of Evi
Slide 6: Locally acting PBPK models
Locally acting PBPK models Oral Cavity (OCCAT™) Ocular (OCAT™) Pulmonary (PCAT™) Dermal (TCAT™) 6
Slide 7: Ocular Compartmental Absorption & Transit model
Ocular Compartmental Absorption & Transit model 7
Slide 8: History of the OCAT Model
History of the OCATTM Model 2008: Initial creation of the OCAT V1 model by Simulations Plus scientist in collaboration with Pfizer 2014-2017: Cooperation grant with the FDA 3-year funded collaborative project with the FDA Office of Generic Drugs on the development of mechanistic models for ocula
Slide 9: 2020: New Collaboration with the FDA
2020: New Collaboration with the FDA 9
Slide 10: The Eye and the OCAT
The Eye and the OCATTM Conjunctiva Vitreous Humor A.H. Cornea ICB Retina Choroid Sclera Sagittal plane 10
Slide 11: Modes of Administration in the Eye
Modes of Administration in the Eye • < 5% reaches anterior 1) Topical segment • Tiny fraction reaches Retina • Penetration is limited by 2) Systemic blood aqueous and blood retinal barriers • Effective mode of administration for achieving 3) Intravitreal therapeutic concentrations in retina • Noninv
Slide 12: Schematic of Drug Disposition from Ocular Doses
Schematic of Drug Disposition from Ocular Doses (implemented in GastroPlus®) Topical Doses Pre-Corneal Area (Tear Film & Sac) Nasolacrimal Drainage (50-100%) Ocular Systemic GI Tract Compartments Circulation (ACAT) Handled through the ACAT model Ocular or Productive Non-productive Absorption Absorpt
Slide 13: OCAT Interface
OCATTM Interface Default physiologies for: • Human • Rabbit • Monkey 13
Slide 14: Compound Specific and Physiological Parameters
Compound Specific and Physiological Parameters Compound Specific Permeability in each eye tissue Systemic absorption rate from vascular eye tissues Melanin binding Protein binding Enzyme and transport parameters Physiological Volume Contact Surface Area between tissues/compartments Flow Rates (tear
Slide 15: Relevant Mechanisms
Relevant Mechanisms • Absorption & transport – Simple Diffusion (transcellular) – Carrier-mediated transport – Convective flow • Metabolism – Linear – Saturable • Melanin binding – Linear – Saturable 15
Slide 16: Ocular Dosage Forms
Ocular Dosage Forms • Topical (delivered to the front of the eye) – Immediate-release (eyedrops; both liquid and suspension; ointment) • Intravitreal – Immediate-release (injections; both liquid and suspension) – Controlled-release (implants) • Other – Subconjunctival implants 16
Slide 17: Capabilities of the Program
Capabilities of the Program • Determine the degree of productive and non-productive absorption and loss • Determine the amount of drug cleared into systemic circulation from the eye • Physiological parameters can be edited from their default values (to reflect specific conditions or disease states)
Slide 18: Ocular Statistics
18 C Ucular Compartme! Ocular Statistics Comp Name Cmax-Obs |Cmax-Cale |Tmax-Obs | Tmax-Cale lan lan lat fear Pre-comea 927.1 1000.0 O07 0.0 472.3 151.4 226.8 151.2 Comed 75.23 83.36 0.030 0.080 41.46 70.15 41.15 70 Conjunctiva 0.0 1.26E-4 =|0.0 3.000 it} 3.21E-4 0.0 0.000321 Aqueous Humor 3.250 4.1
Slide 19: Case Study: Fluorometholone
Case Study: Fluorometholone 19
Slide 20: Background and Aims
Background and Aims • Background - Tobradex® 0.1% Dexamethasone - Tobradex ST® 0.05% Dexamethasone Aqueous humor exposure is similar despite the strength differences. Same particle size (PS) but difference in viscosity (75 cps for Tobradex ST® and 1.5 cps for Tobradex®) • Aims – Verify an OCAT™ mo
Slide 21: Modeling Strategy
Modeling Strategy Model Model New Development Validation Formulation 4.10-5 M Solution of 0.4% Flm Suspension C. epithelium AH PS = 6 µm Requirements Cornea Safety: Dose= 0.01% PS < 10 µm 0.1% Efficacy: Suspension PS = 10.4 µm AH exposure comparable C. Stroma AH to the 0.1% Suspension; AH PS=
Slide 22: Summary: Model Development
Summary Model Development 4.10-5 M Solution of Flm 22 Sieg-J Pharm Sci-Sep-70-9-1026-9-1981
Slide 23: Summary: Model Validation
Summary Model Validation 0.1% 0.4% Suspension Suspension PS = 10.4 PS = 6 µm µm 23 Hui-Robinson-JPharmSci-73-3-280-1986
Slide 24: New Formulation
New Formulation Requirements Safety: PS = 2 µm Dose= 0.01% Drainage rate = 0.4 PS < 10 m Efficacy: AH exposure comparable to the 0.1% Suspension; PS = 10.4 µm Suspension 0.1%; AH AUC 0.491 PS = 10.4 µm (µg.h/mL) AH AUC 0.480 Cmax (µg/mL) 0.111 (µg.h/mL) Cmax 0.108 (µg/mL) 24 Patton-Robinson-JP
Slide 25: To learn More:
To learn More: [Protocol for evaluation of topical ophthalmic drug products in different compartments of fresh eye tissues in a rabbit model Asho Jiang U.S. Fede Application of Mechanistic Ocular Absorption Modeling and Simulation to Understand the Impact of Formulation Properties on Ophthalmic Bioa
Slide 26: To learn More (bis):
To learn More (bis): https://www.youtube.com/watch?v=IoNeSlUN-4Q&t=2406s&ab_channel=SimulationsPlus%2CInc. 26
Slide 27: Pulmonary Compartmental Absorption & Transit model
Pulmonary Compartmental Absorption & Transit model 27
Slide 28: 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.
Slide 29: Processes Involved in Nasal-Pulmonary Absorption
Processes Involved in Nasal-Pulmonary Absorption These phenomena: • are happening simultaneously • are repeated in each of the compartments of the nasal-pulmonary model 29
Slide 30: Pulmonary Compartmental Absorption and Transit Model
Pulmonary Compartmental Absorption and Transit Model Default physiologies for: • Human • Rat • Mouse • Dog
Slide 31: Compound Specific and Physiological Parameters
Compound Specific and Physiological Parameters Compound Specific • Permeability in each tissue • Metabolic clearance • Systemic absorption rate from nasal-pulmonary tissues • Mucus/cell binding • Enzymes & Transporters tabs Physiological • Surface Area • Mucus Layer Thickness • Epithelial Thickness
Slide 32: Distribution of Dose into Pulmonary Compartments
Distribution of Dose into Pulmonary Compartments Dose Amt in ET1 = Amt in ET2 = Amt in BB = Amt in bb = Amt in AI = fET1 X Dose fET2 X Dose fBB X Dose fbb X Dose fAI X Dose Nose Extra-thoracic Thoracic Bronchiolar Alveolar • The fractions (fET1 to fAI) can be – Calculated (dependent, e.g., on partic
Slide 33: Regional Deposition Calculation
Regional Deposition Calculation Regional lung deposition can be predicted (from particle size distribution, standard deviation, etc. using the ICRP66 or Finlay deposition model) or specified manually by the user Output (% deposited) that distributes the administered dose into different lung compartm
Slide 34: Nasal-Pulmonary Dosage Forms
Nasal-Pulmonary Dosage Forms Dosage Form Dosing Dosing Form Physical State Name Compartment Type PL: Soln Distributed Immediate Liquid PL: Powder Distributed Immediate Solid PL: IT Soln Thoracic Immediate Liquid PL: IT Powder Thoracic Immediate Solid PL: Nasal Soln Nose Immediate Liquid PL: Nasal Po
Slide 35: Specific Nasal-Pulmonary Capabilities
Specific Nasal-Pulmonary Capabilities • Evaluation of the independent contribution of pulmonary and gut absorption after inhaled administration • Evaluation of formulation effects (dosage form, particle size, distribution, density, shape factor, presence of excipient, etc...) • Additional mechanisms
Slide 36: Selected Pulmonary Example (1)
Selected Pulmonary Example (1) B Fitted pulmonary permeability against in vivo adult data and used to predict PK in children Lukacova V, Poster presentation, Rosenon Meeting 2010, Stockholm, Sweden, Sept 9-11, 2010
Slide 37: Selected Pulmonary Example (2)
Selected Pulmonary Example (2) Building the model: PulmoSphere Applying the model: TOBI
Slide 38: To learn More:
To learn More: https://www.youtube.com/watch?v=fnkbENLMGuY&ab_channel=SimulationsPlus%2CInc. 38
Slide 39: Pharmacodynamics
Pharmacodynamie 39
Slide 40: Entering the era of computationally driven drug development
Entering the era of computationally driven drug development Neha Maharao’, Victor Antontsev®, Matthew Wright? and Jyotika Varshney* VeriSIM Life Inc., San Francisco, CA, USA; PDMPK, Genentech Inc., San Francisco, CA, USA Loss or stimulation : Kin | 7 — a ———N Respons: :) = 6: Boston | Cy mm SS Loss
Slide 41: PK/PD
PK/PD ‘what the body does to the drug’ ‘what the drug does to the body’ PK/PD: link pharmacokinetics and pharmacodynamics in order to establish a dose- concentration-response relationship and subsequently describe and predict the effect- 41 time course resulting from a drug dose
Slide 42: PDPlus Module
PDPlus™ Module Standard Jusko/Derendorf pharmacodynamic models: • Direct • Linear • Log-linear • Emax • Sigmoid Emax • Indirect • Indirect Link: Effect compartment • Class I – IV • Cell killing • Bacterial kill and growth (power & sigmoidal model) • Precursor dependent (indirect models V – VIII) 42
Slide 43: Direct Response Models
Direct Response Models • Linear E = E0 + S*C • Log linear E = E0 + S*log(C) • Emax E = E0 + Emax * C / (EC50 + C) E = E0 - Imax * C / (IC50 + C) [inhibition] • Sigmoid Emax γ γ γ E = E0 + Emax * C / (EC50 + C ) γ γ γ E = E0 - Imax * C / (IC50 + C ) [inhibition] C = Concentration E = Effect E0 = Base
Slide 44: Sigmoid Emax Model
44 PD Effect Potency more} less ECs v T rT rT Tr Concentration SimulationsPlus ‘SCIENCE + SOFTWARE = SUCCESS
Slide 45: Direct vs. Indirect
Direct vs. Indirect Direct Indirect: Hysteresis Counter clockwise Clockwise Mechanistic Explanations for Hysteresis Counter-clockwise Clockwise Distribution delay between the plasma and effect site Indirect effects: Indirect effects: • Stimulation of input • Inhibition of input • Inhibition of outpu
Slide 46: Indirect Models in PDPlus
Indirect Models in PDPlus™ Indirect Link: Effect compartment: Sigmoid Emax model, but Ce instead of Cp Class I - inhibition of buildup: Drug inhibits transfer of drug into effect compartment Class II - inhibition of dissipation: Drug inhibits transfer of drug out of effect compartment Class III - st
Slide 47: Indirect Link - Class I-IV
Indirect Link - Class I-IV Drug Incoming action response Tissue Response Net drop in Drug response action 𝑑𝑑𝑑𝑑 𝐼𝐼max . 𝐶𝐶 𝐸𝐸max . 𝐶𝐶 𝐼𝐼max . 𝐶𝐶 𝐸𝐸max . 𝐶𝐶 = 𝐾𝐾𝑖𝑖𝑖𝑖 1 − . 1− − 𝐾𝐾𝑜𝑜𝑜𝑜𝑜𝑜 1 − . 1− 𝑅𝑅 𝑑𝑑𝑑𝑑 𝐼𝐼𝐶𝐶50 + 𝐶𝐶 𝐸𝐸𝐶𝐶50 + 𝐶𝐶 𝐼𝐼𝐶𝐶50 + 𝐶𝐶…
Slide 48: Indirect Link Bacteria Killing and Growth Model
Indirect Link Bacteria Killing and Growth Model The model consists of two bacterial population: one susceptible and one pre-existing resistant 48 From Kristoffersson (Pharm Res. 2016)
Slide 49: Precursor-dependent Indirect Model
Precursor-dependent Indirect Model k0: the zero-order rate constant for precursor production kp: the first-order rate constant for production of the response variable ks and kout: first-order rate constants for loss of the precursor or response H1: the inhibition or stimulation of precursor producti
Slide 50: Building PK/PD Models
Building PK/PD Models Select multiple records Select the effect compartment Select the PD model 5050
Slide 51: Thank you!
51 Thank you! @B Simulations SCIENCE + SOFTWARE = SUCCESS
Slide 52: For More Information:
For More Information: Visit our website at: www.simulations-plus.com Email: maxime@simulations-plus.com Thank you! 52
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