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Case studies with mrgsolve: PBPK and QSP model implementation and utilization in R

https://github.com/metrumresearchgroup/pbpk-qsp-mrgsolve

CDSE Days 2018

Optimization in R with mrgsolve

https://github.com/metrumresearchgroup/ub-cdse-2019

• mrgsolve intro
• The R “way” to do optimization (simple linear model)
• Indomethacin PK model optimization
• Pitavastatin / CsA DDI model optimization
• Look at options for different optimizers
• Local sensitivity analysis
• Likelihood profile
• Generate virtual population

Single level of random effects

• Today, optimizing parameters for models with single level of random effects (no IIV)
• Options are available: nlme, saemix
  • Use if really needed (like here)
• Look at nlmixr for multi-level modeling in R with ODEs

About mrgsolve

• R package for simulation from ODE-based models
  • Free, OpenSource, GitHub, CRAN
• Language
  • Models written in C++ inside model specification format
  • General purpose solver: ODEPACK / DLSODA (FORTRAN)
    • Automatically detect and switch between non-stiff (Adams) and stiff (BDF) methods for solving the differential equations
  • Simulation workflow in R
• Hierarchical (population) simulation
  • ID, \(\eta\), \(\varepsilon\)
• Integrated PK functionaility
  • Bolus, infusion, F, ALAG, SS etc, handled under the hood
  • 1- and 2-cmt PK models in closed-form
• Extensible using R, C++, Rcpp, boost, RcppArmadillo
• R is it’s natural habitat

mrgsolve started as QSP modeling tool

• Motivation: large bone/mineral homeostatsis model (CaBone)
• History using
  • Berkeley Madonna
  • WinBUGS
  • NONMEM (attempted)
• 2010: write R front end to deSolve
• 2012: write C++ interface to DLSODA
• Develop dosing / event capability
• More recently, expose functionality provided by
  • Rcpp - vectors, matrices, functions, environments, random numbers
  • boost - numerical tools in C++
  • users’ own C++ code (functions, data structures, classes)
• Translator from SBML to mrgsolve using R bindings to libSBML

Orientation

• https://CRAN.R-project.org/package=mrgsolve

• GitHub site: https://github.com/metrumresearchgroup/mrgsolve

• Issues and questions: https://github.com/metrumresearchgroup/mrgsolve/issues

• mrgsolve website: https://mrgsolve.github.io

• User Guide: https://mrgsolve.github.io/user_guide

• Blog: https://mrgsolve.github.io/blog

• Vignettes: https://mrgsolve.github.io/vignettes

Optimization - log likelihood function

Optimization - log likelihood function

Optimization - log likelihood function

Optimization - log likelihood function

Optimization - log likelihood function

Wonderful options for optimization in R

CRAN Task View: https://cran.r-project.org/web/views/Optimization.html