Target-mediated drug-disposition (TMDD) model comparison using the MonolixSuite
Geraldine Ayral (1), Jonathan Chauvin (1)
(1) Lixoft, Antony, France
Objectives: The increase of biologic drugs in development leads to a rise of the use of target-mediated drug disposition (TMDD) models to describe their kinetics. As the original full TMDD [1] model is often overparametrized, a number of approximations have been proposed (see [2] for a review). The workload of implementing the differential equations representing these approximations hampers the testing of a large range of approximations to find the best one. We here propose an extensive comparison and explanation of the hierarchy of TMDD model approximations, as well as guidelines to choose an appropriate model.
Methods: For the comparison, we have developed a library of TMDD models that contains 608 model files, corresponding to the combination of the following options:
- Model/approximation: full, QSS, QE, irreversible binding, constant Rtot, Wagner, MM
- Administration type: bolus, infusion, first-order absorption, zero-order absorption
- Number of compartments: 1 or 2
- Parametrization: using elimination rates or clearances
- Presence of a lag time for the absorption: yes or no
- Output considered: free ligand, free+bound ligand or custom output
A comparison in terms of response w.r.t. time of these models is proposed along with the impact of each parameter of the concentration-time curves.
Results: Using the Mlxplore application from the MonolixSuite, we explore the behavior of each model/approximation using a sensitivity analysis approach. This permits to derive a summary scheme of the behavior and limitations of each approximation compared to the full original model, thereby greatly helping in the choice of an appropriate model depending on prior knowledge and the data characteristics. Guidelines to choose a first model and improve it based on diagnostic graphics are given.
Conclusions: The availability of a large number of ready-to-use TMDD models, together with an extensive comparison of concentration-time curves, will help modelers to find the best model for their data with no implementation work, thus contributing to efficient and reliable modeling results.
References:
[1] Mager, D. E., & Jusko, W. J. (2001). General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. Journal of Pharmacokinetics and Pharmacodynamics, 28(6), 507–32.
[2] Dua, P., Hawkins, E., & van der Graaf, P. (2015). A Tutorial on Target-Mediated Drug Disposition (TMDD) Models. CPT: Pharmacometrics & Systems Pharmacology, 4(6), 324–337.
