Abstract
Nonlinear ordinary differential equations (ODEs) are common in pharmacokinetic–pharmacodynamic systems. Although their exact solutions cannot generally be determined via algebraic methods, their rapid and accurate solutions are desirable. Thus, numerical methods have a critical role.
Inductive Linearization
was proposed as a method to solve systems of nonlinear ODEs. It is an iterative approach that converts a nonlinear ODE into a linear time-varying (LTV) ODE, for which a range of standard integration techniques can then be used to solve (e.g.,
eigenvalue decomposition
[EVD]). This study explores the properties of
Inductive Linearization
when coupled with EVD for integration of the LTV ODE and illustrates how the efficiency of the method can be improved. Improvements were based on three approaches, (1) incorporation of a convergence criterion for the iterative linearization process (for simulation and estimation), (2) creating more efficient step sizes for EVD (for simulation and estimation), and (3) updating the initial conditions of the
Inductive Linearization
(for estimation). The performance of these improvements were evaluated using single subject stochastic simulation-estimation with an application to a simple pharmacokinetic model with Michaelis–Menten elimination. The reference comparison was a standard non-stiff Runge–Kutta method with variable step size (
ode45
, MATLAB). Each of the approaches improved the speed of the
Inductive Linearization
technique without diminishing accuracy which, in this simple case, was faster than
ode45
with comparable accuracy in the parameter estimates. The methods described here can easily be implemented in standard software programme such as R or MATLAB. Further work is needed to explore this technique for estimation in a population approach setting.