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. 2019 Sep;8(9):621-633.
doi: 10.1002/psp4.12445. Epub 2019 Jul 16.

Nonlinear Mixed-Effects Model Development and Simulation Using nlmixr and Related R Open-Source Packages

Matthew Fidler  1 , Justin J Wilkins  2 , Richard Hooijmaijers  3 , Teun M Post  3 , Rik Schoemaker  2 , Mirjam N Trame  4 , Yuan Xiong  5 , Wenping Wang  6
Affiliations

Nonlinear Mixed-Effects Model Development and Simulation Using nlmixr and Related R Open-Source Packages

Matthew Fidler et al. CPT Pharmacometrics Syst Pharmacol. 2019 Sep.

Abstract

nlmixr is a free and open-source R package for fitting nonlinear pharmacokinetic (PK), pharmacodynamic (PD), joint PK-PD, and quantitative systems pharmacology mixed-effects models. Currently, nlmixr is capable of fitting both traditional compartmental PK models as well as more complex models implemented using ordinary differential equations. We believe that, over time, it will become a capable, credible alternative to commercial software tools, such as NONMEM, Monolix, and Phoenix NLME.

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Conflict of interest statement

The authors declared no competing interests for this work.

Figures

Figure 1
Figure 1
Basic goodness‐of‐fit plots for the final model including covariates. Blue points are observations. Blue lines represent individuals. Red lines are loess smooths through the data. Black lines are lines of identity. CWRES, conditional weighted residuals. DV represents the observations, PRED the predictions, IPRED the individual predictions.
Figure 2
Figure 2
Visual predictive check for the final model including covariates. Black points are original observations. Solid black line is the observed median, by bin. Dashed black lines represent observed 5th and 95th percentiles, by bin. Blue shaded areas represent 90% confidence intervals around simulated 5th, 50th, and 95th percentiles. Binning at 0, 3, 12, 24, 168, 171, 180, and 192 hours. N = 700 iterations.
Figure 3
Figure 3
RxODE simulation of final model.
Figure 4
Figure 4
The shinyMixR interface. OBJF is the objective function value; dOBJF is the change in objective function value.
See this image and copyright information in PMC

References

    1. Lalonde, R.L. et al Model‐based drug development. Clin. Pharmacol. Ther. 82, 21–32 (2007). - PubMed
    1. Grasela, T.H. et al Pharmacometrics and the transition to model‐based development. Clin. Pharmacol. Ther. 82, 137–142 (2007). - PubMed
    1. Barrett, J.S. , Fossler, M.J. , Cadieu, K.D. & Gastonguay, M.R. Pharmacometrics: a multidisciplinary field to facilitate critical thinking in drug development and translational research settings. J. Clin. Pharmacol. 48, 632–649 (2008). - PubMed
    1. Mould, D.R. , D'Haens, G. & Upton, R.N. Clinical decision support tools: the evolution of a revolution. Clin. Pharmacol. Ther. 99, 405–418 (2016). - PubMed
    1. Helmlinger, G. et al Drug‐disease modeling in the pharmaceutical industry ‐ where mechanistic systems pharmacology and statistical pharmacometrics meet. Eur. J. Pharm. Sci. 109, S39–S46 (2017). - PubMed