Section: Application Domains

Population pharmacometrics

(joint project with Lixoft)

Pharmacometrics involves the analysis and interpretation of data produced in pre-clinical and clinical trials. Population pharmacokinetics studies the variability in drug exposure for clinically safe and effective doses by focusing on identification of patient characteristics which significantly affect or are highly correlated with this variability. Disease progress modeling uses mathematical models to describe, explain, investigate and predict the changes in disease status as a function of time. A disease progress model incorporates functions describing natural disease progression and drug action.

The model based drug development (MBDD) approach establishes quantitative targets for each development step and optimizes the design of each study to meet the target. Optimizing study design requires simulations, which in turn require models. In order to arrive at a meaningful design, mechanisms need to be understood and correctly represented in the mathematical model. Furthermore, the model has to be predictive for future studies. This requirement precludes all purely empirical modeling; instead, models have to be mechanistic.

In particular, physiologically based pharmacokinetic models attempt to mathematically transcribe anatomical, physiological, physical, and chemical descriptions of phenomena involved in the ADME (Absorption - Distribution - Metabolism - Elimination) processes. A system of ordinary differential equations for the quantity of substance in each compartment involves parameters representing blood flow, pulmonary ventilation rate, organ volume, etc.

The ability to describe variability in pharmacometrics model is essential. The nonlinear mixed-effects modeling approach does this by combining the structural model component (the ODE system) with a statistical model, describing the distribution of the parameters between subjects and within subjects, as well as quantifying the unexplained or residual variability within subjects.

The objective of Xpop is to develop new methods for models defined by a very large ODE system, a large number of parameters and a large number of covariates. Contributions of Xpop in this domain are mainly methodological and there is no privileged therapeutic application at this stage [7], [21], [14].

However, it is expected that these new methods will be implemented in software tools, including Monolix and Rpackages for practical use.