Simulations Plus, Inc. · NASDAQ:SLP
Simulations Plus — AAPS PharmSci 360 2018
11 slides from Simulations Plus's conference presentation, Nov 5, 2018
Slide 1: HTPK: Conducting PK modeling and simulations at high speed
HTPK: Conducting PK modeling and simulations at high speed November 5, 2018 Robert Fraczkiewicz, David Miller, Marvin Waldman, Robert D. Clark Slide 1 #PharmSci360
Slide 2: Session Description and Objectives
Session Description and Objectives • HTPK lightens the burden of • Objective: To compare predicted collecting and preparing input percent absorbed and percent variables for full blown PK bioavailable between the high simulations by using structure- throughput PK (HTPK) simulation based predictions.
Slide 3: Biography and Contact Information
Biography and Contact Information • Research Fellow at Simulations Plus, Inc. • 20 years of experience in predictive molecular modeling and related software development. • Author of the HTPK module. • Robert@simulations-plus.com Slide 3 #PharmSci360
Slide 4: Advanced Compartmental Absorption and Transit (ACAT) model used by HTPK
Advanced Compartmental Absorption and Transit (ACAT™) model used by HTPK Central compartment • A system of 28 nonlinear ordinary differential equations Slide 4 #PharmSci360
Slide 5: HTPK inputs
HTPK inputs Input required for %Fa and %Fb Corresponding ADMET Predictor model Diffusivity in water DiffCoef Solubility in water S+Sw Salt solubility factor SolFactor Solubility in fasted intestinal fluid S+FaSSIF Solubility in fed intestinal fluid pKa S+FeSSIF S+pKa • Any of the predicted Human jej
Slide 6: HTPK outputs
HTPK outputs Outputs generated by the %Fa/%Fb model Fraction absorbed Fraction bioavailable Cp(t) = plasma concentration vs. time profile C_max = maximum plasma concentration t_max = time of peak plasma concentration AUC = area under the Cp(t) curve Sensitivity to permeability and solubility Mechani
Slide 7: HTPK caveats
HTPK caveats • The dose is fixed as an immediate release tablet. • Any precipitate is presumed to have the same particle size as the original dosage form. The particle size is 25 µm by default but can be adjusted. Precipitation process is described by simpler equations in HTPK. • Liver metabolism re
Slide 8: HTPK performance
HTPK performance • Calculation of fraction absorbed and fraction bioavailable in human after 24 h at three different IR doses: 1 mg, 10 mg, and 100 mg. • 2284 diverse drugs extracted from World Drug Index. Processing time for (*) • A = DELL XPS with Intel® Platform (*) 2284 drugs Core™ i7-3537U CPU
Slide 9: HTPK validation %Fa %Fb
HTPK validation %Fa and %Fb at 10 mg dose HTPK results compared against compartmental PK results obtained in GastroPlus™ v9.6 for a subset of 300 drugs extracted from the World Drug Index. precipitation %Fa %Fb Slide 9 #PharmSci360
Slide 10: HTPK validation against observed human data
HTPK validation Predicted and observed human %Fa for 115 passively-absorbed compounds Predicted and observed human %Fb for 62 compounds metabolized primarily by published in [Zhao et al. J. Pharm. Sci., 2001, 90: 749.] 90% predicted were hepatic CYPs [Toshimoto et al. Drug Metab. Dispos. 2014, 42:18
Slide 11: Questions
Questions Slide 11 #PharmSci360