Jason Chittenden (1), Nidal Huniti (1), Jenny Nguyen (1), Kamal Srinivasn (1), Ian Linsmeier (2)
(1) Regeneron Pharmaceuticals, USA, (2) A2PG Consultants, USA
Introduction: TablerPMX is an open-source Shiny[1] application, freely available on GitHub [2], for the simulation of pharmacokinetic (PK) models. It implements a user-friendly interface to input model parameters, dosing regimen, and settings for simulations from a library of models. The application utilizes mrgsolve [3], an R package for simulation from hierarchical, ordinary differential equation (ODE) based models typically employed in drug development, for model description and simulation, providing a convenient and popular method for expressing models and rapid calculation over the large numbers of subjects in population simulations. TablerPMX presents results on screen, with plots of the typical subject and population simulations and summary of key PK parameters, and in a downloadable report.
TablerPMX is under active development, with the following key features currently implemented:
- Selection of a PK model from a library that includes variations of linear and non-linear elimination, multiple compartments, target mediated drug disposition, and absorption compartment,
- The ability to load a custom user-defined model in the form of an mrgsolve model file,
- A graphical user interface (GUI) for entering fixed and random effect parameters, dosing regimen (using mrgsolve “doseRx” syntax), and simulation settings,
- Review of plots and tables on-screen and in a downloadable report, and
- The ability to download dosing and simulation tables for further analysis.
Objectives:
- Provide an easy to use, GUI-based tool for simulating from PK models
- Demonstrate TablerPMX by simulating a dupilumab model from literature
Methods: TablerPMX was developed primarily based on the R Shiny and mrgsolve packages. The GUI consists of 5 main tabs: Model Selection; Simulation Details; Simulation Output; Report Generation; and Documentation. A literature model for dupilumab[4] was selected to demonstrate the simulation workflow. On the Model Selection tab, a two-compartment model with linear and non-linear elimination and first order absorption was selected. The model parameters were entered in the dialog windows that appear when clicking on the Fixed Effects and Random Effects buttons. The dosing for two regimens — s.c.: 300 mg q2w (with a 600 mg loading dose) and 200 mg q2w (with a 400 mg loading dose) – was entered on the Simulation Details tab. The Simulation Settings were changed to 1 replicate of 1000 subjects. The simulation was completed, and a report was generated.
Results: The simulated profiles (median and 95% prediction interval) were consistent with the published phase 3 results in the publication[x]. The mean (SD) Cmax, Tmax, and AUC were: 132 (74) mg/L , 3.2 (1.1) days, and 7342 (845) mg/L*day for the 200 q2W regimen; and 279 (96) mg/L , 3.3 (1.2) days, and 8198 (1375) mg/L*day for the q4W regimen.
Conclusion: TablerPMX provides an easy-to-use interface for simulating many common PK models. The application was able to reproduce results from a published PK model. TablerPMX may prove useful to modelers and non-modeler colleagues who wish to quickly evaluate new dosing regimens and or covariate effects in existing models without having to implement the simulation code and model translations (e.g. from NONMEM) themselves.
References:
[1] Winston Chang, Joe Cheng, JJ Allaire, Carson Sievert, Barret Schloerke, Yihui Xie, Jeff Allen, Jonathan McPherson, Alan Dipert and Barbara Borges (2021). shiny: Web Application Framework for R. R package version 1.7.1. https://CRAN.R-project.org/package=shiny
[2] https://github.com/
[3] Kyle T Baron (2022). mrgsolve: Simulate from ODE-Based Models. R package version 1.0.3.
https://CRAN.R-project.org/package=mrgsolve
[4] Zhang L, Gao Y, Li M, Xu C, Davis JD, Kanamaluru V, Lu Q. Population pharmacokinetic analysis of dupilumab in adult and adolescent patients with asthma. CPT Pharmacometrics Syst Pharmacol. 2021 Aug;10(8):941-952. doi: 10.1002/psp4.12667. Epub 2021 Jul 27. PMID: 34313019; PMCID: PMC8376131.
Reference: PAGE 30 (2022) Abstr 10217 [www.page-meeting.org/?abstract=10217]
Poster: Software Demonstration