Implementation of non-linear mixed effects models defined by fractional differential equations.

Fractional differential equations (FDEs), i.e. differential equations with derivatives of non-integer order, can describe certain experimental datasets more accurately than classic models and have found application in pharmacokinetics (PKs), but wider applicability has been hindered by the lack of appropriate software. In the present work an extension of NONMEM software is introduced, as a FORTRAN subroutine, that allows the definition of nonlinear mixed effects (NLME) models with FDEs. The new subroutine can handle arbitrary user defined linear and nonlinear models with multiple equations, and multiple doses and can be integrated in NONMEM workflows seamlessly, working well with third party packages. The performance of the subroutine in parameter estimation exercises, with simple linear and nonlinear (Michaelis-Menten) fractional PK models has been evaluated by simulations and an application to a real clinical dataset of diazepam is presented. In the simulation study, model parameters were estimated for each of 100 simulated datasets for the two models. The relative mean bias (RMB) and relative root mean square error (RRMSE) were calculated in order to assess the bias and precision of the methodology. In all cases both RMB and RRMSE were below 20% showing high accuracy and precision for the estimates. For the diazepam application the fractional model that best described the drug kinetics was a one-compartment linear model which had similar performance, according to diagnostic plots and Visual Predictive Check, to a three-compartment classic model, but including four less parameters than the latter. To the best of our knowledge, it is the first attempt to use FDE systems in an NLME framework, so the approach could be of interest to other disciplines apart from PKs.