Simulations Plus, Inc. · NASDAQ:SLP
Simulations Plus — Technical Presentation (February 2023)
28 slides from Simulations Plus's technical presentation, Feb 13, 2023
Slide 1: Use of QSAR-based PBPK models for Regulatory Exposure Assessments
Use of QSAR-based PBPK models for Regulatory Exposure Assessments Michael Bartels, Ph.D. ToxMetrics.com LLC MB 02/16/2023 1
Slide 2: Outline
PBPK models for Regulatory Exposure Assessments Outline - PBPK modeling needs for chemical registrations - Evaluation of GastroPlus™ for prediction of physical- chemical and pharmacokinetic parameters - Case Study #1- PBPK modeling of TCVP dermal penetration - Case Study #2- Dermal and Inhalation ab
Slide 3: Variety of modeling approaches used during product development and registrations
PBPK models for Regulatory Exposure Assessments Pre- Post Re- Discovery Development Development Registration Registration High-end PBPK models (interspecies & multiple routes) In silico Opportunity: Standardize modeling approaches Toxicokinetic modeling Preliminary In silico High PBPK model throughp
Slide 4: Modeling software criteria
PBPK models for Regulatory Exposure Assessments Modeling software criteria: Support for multiple exposure routes and regimens Oral, Dermal and Inhalation (critical for Chemical Risk Assessments) Acute, steady-state Incorporates critical QSARs for: Absorption rates and amounts Metabolic clearance and
Slide 5: Modeling software criteria: validation plan
PBPK models for Regulatory Exposure Assessments Modeling software criteria: • GastroPlus validated primarily with pharmaceutical compounds • delivered via the oral route • Needed to validate QSAR and PK / PBPK predictions for: • Broad range of chemistries for non-pharmaceuticals • Oral, Dermal, Inha
Slide 6: Experimental vs. Predicted pKa Values
PBPK models for Regulatory Exposure Assessments Experimental vs. Predicted pKa Values from ADMET Predictor model of GastroPlus™ (ADMET) or Pipeline Pilot™ (PP) The predicted pKa values from ADMET correlated well with the literature data and were better than those predicted by PP MB 02/16/2023 6
Slide 7: Experimental vs. Predicted LogP Values
PBPK models for Regulatory Exposure Assessments Experimental vs. Predicted LogP Values from ADMET Predictor model of GastroPlus™ (ADMET) or US EPA EpiSuite The predicted LogP values from ADMET correlated well with the literature data and were comparable to those predicted by EpiSuite MB 02/16/2023 7
Slide 8: Accuracy of PK parameter predictions
PBPK models for Regulatory Exposure Assessments Accuracy of PK parameter predictions Clint Fraction Unbound in Plasma Percent (%) Fold difference from Percent of the total Percent of the total difference from empirical data compounds * compounds ** empirical data 1 to 3 38% 1 to 10 61% 3 to 10 29% 1
Slide 9: Accuracy of Steady-State Systemic Exposure predictions
PBPK models for Regulatory Exposure Assessments Accuracy of Steady-State Systemic Exposure predictions Comparison of GastroPlus Prediction Results with Published IVIVE Modeling Results (oral route) Reference PK or Restrictive hepatic GastroPlus GastroPlus Predicted PBPK derived clearance Predicted (
Slide 10: Prediction of Saturable Oral Absorption in Rat
PBPK models for Regulatory Exposure Assessments 1 Prediction of Saturable 0.9 Oral Absorption in Rat 0.8 0.7 - Comparison between 0.6 Fraction Absorbed compartmental GI tract model (GastroPlus) and 0.5 algebraic fit-to-data 0.4 approach (Dolton 2017) 0.3 0.2 0.1 0 0.01 0.1 1 10 100 1000 External Con
Slide 11: Case Study #1 with Tetrachlorvinphos
PBPK models for Regulatory Exposure Assessments Case Study #1 with Tetrachlorvinphos MB 02/16/2023 11
Slide 12: Risk assessments based on rat dermal toxicity studies
PBPK models for Regulatory Exposure Assessments Risk Assessments for chemicals are often based on dermal toxicity studies conducted in rats/mice These assessments may be conservative, due to known higher permeability of rat skin vs. human skin - Differences in permeability are consistent with specie
Slide 13: Prediction of Dermal Absorption: TCVP
PBPK models for Regulatory Exposure Assessments Prediction of Dermal Absorption: 40 Percent Dermal Absorption Rat in silico 27.9% - Species and dose- dependent differences for 30 Rat in vitro 21.7% TCVP Rat in vivo 20.0% Human in silico - Correlation of saturable 20 Human in vitro absorption in rat
Slide 14: Case Study #2 with Modified MDI Substances
PBPK models for Regulatory Exposure Assessments Case Study #2 with Modified Methylene diphenyl diisocyante (MDI) Substances MB 02/16/2023 14
Slide 15: Read Across Assessment Framework (EU ECHA 2017)
PBPK models for Regulatory Exposure Assessments Read Across Assessment Framework (EU ECHA 2017) - “‘Read-across and grouping’, or ‘read- across’, is one of the most commonly used alternative approaches for data gap filling in registrations submitted under the REACH Regulation. Read-across involves t
Slide 16: Read Across Assessment for Modified MDI Substances
PBPK models for Regulatory Exposure Assessments Read Across Assessment for 39 Modified MDI Substances Substances 1-3 MWT 250 All substances quite lipophilic and contain at least two Substances 4, 7 reactive isocyanate moieties Substances 5, 6, 18, 19 MB 02/16/2023 Substances 8-17, 20-39 MWT up to 21
Slide 17: Read Across Assessment: PBPK modeling approach
PBPK models for Regulatory Exposure Assessments Read Across Assessment for 39 Modified MDI Substances Assessment includes evaluation of the relative absorption of 39 substances via dermal and inhalation exposure routes • Gastro Plus-based PBPK modeling therefore conducted via the dermal and inhalati
Slide 18: Predicted Log P and Water Solubility vs Molecular Weight
PBPK models for Regulatory Exposure Assessments Read Across Assessment for 39 Modified MDI Substances Physical-chemical properties required for PBPK parameter derivations were first determined with QSAR-based approaches due to the low water solubility and reactivity of the substances Predicted Log W
Slide 19: Dermal absorption prediction optimization
PBPK models for Regulatory Exposure Assessments Read Across Assessment for 39 Modified MDI Substances Evaluation of dermal absorption for Testosterone Optimization of dermal absorption predictions for (in vivo data from Bartek 1972) 4,4’-MDI in rat (in vivo data from Leibold 1999) 100 Percent System
Slide 20: Dermal penetration of selected MDI substances through human skin
PBPK models for Regulatory Exposure Assessments Compound 1 Compound 2 Compound 3 Compound 4 100 100 100 100 Dermal penetration of Percent of Dose Percent of Dose Percent of Dose Percent of Dose 10 10 10 10 1 selected MDI 0.1 1 1 1 0.1 0.1 0.1 substances through 0.01 0.01 0.01 0.01 compartments of 20
Slide 21: Percent Dermal Uptake/Absorption by carrier solvent
PBPK models for Regulatory Exposure Assessments Read Across Assessment for 39 Modified MDI Substances Test substance in acetone carrier solvent Test substance in octanol carrier solvent (8 hr exposure to human skin) (8 hr exposure to human skin) 2500 2500 Percent Dermal Uptake/Absorption Percent Der
Slide 22: Optimization of pulmonary/oral absorption predictions for 4,4'-MDI
PBPK models for Regulatory Exposure Assessments Read Across Assessment for 39 Modified MDI Substances Optimization of pulmonary/oral absorption predictions for 4,4’-MDI in rat following Percent Systemically Bioavailable 100 Measured (Gledhill 2005) inhalation exposure to 14C-test substance Predicted
Slide 23: Predicted pulmonary / oral absorption in human
PBPK models for Regulatory Exposure Assessments Read Across Assessment for 39 Modified MDI Substances Predicted pulmonary / Oral Absorption of 60 2500 parent MDI substances in human: Percent Absorbed via Lung / GI • 6 hr inhalation exposure to 0.01 ppm in 2000 air (2.5 µm particle size) Molecular We
Slide 24: Impact of metabolic / chemical clearance on uptake
PBPK models for Regulatory Exposure Assessments Impact of metabolic / chemical clearance on total uptake in human from inhalation exposure 4,4'-MDI Inhalation in Human (6 hr x 0.01 ppm) 10x Lower Clmetabolism / Chemical Hydrolysis 10x Higher Clmetabolism / Chemical Hydrolysis 60 60 60 Percent Absorb
Slide 25: Effect of particle size on pulmonary absorption
PBPK models for Regulatory Exposure Assessments Read Across Assessment for 39 Modified MDI Substances 60 1 µm Predicted pulmonary / Oral Absorption of 2.5 µm Percent Absorbed via Lung parent MDI substances in human: 10 µm • 6 hr inhalation exposure to 0.01 ppm in 40 25 µm air 100 µm • Test substance
Slide 26: Summary
PBPK models for Regulatory Exposure Assessments Summary • GastroPlus has been shown to provide useful predictions of physical-chemical and metabolic properties, as well as estimates of test substance absorption via the oral, dermal or inhalation exposure routes. • Saturable oral and dermal absorptio
Slide 27: References
PBPK models for Regulatory Exposure Assessments References • Bartek, M.J., Labudde, J.A., Maibach, H.I., 1972. Skin permeability in vivo: comparison in rat, rabbit, pig and man. Journal of Investigative Dermatology 58, 114–123. • Bartels, M., van Osdol, W., Le Merdy, M., Chappelle, A., Kuhl, A., Wes
Slide 28: Acknowledgements
PBPK models for Regulatory Exposure Assessments Acknowledgements Dow Chemical International Isocyanate Institute Fagen Zhang Anne Chappelle Amy Clark Robert West Tim Erskine Adam Kuhl Tyler Auernhammer Patrick Pleheirs B. Bhhatarai (Novartis) Dan Wilson Hartz Sue Marty J. Driver W. Reifenrath Simula
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