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Methods

The MTX pharmacokinetic parameters used in the simulations were determined by fitting a two-compartment pharmacokinetic model with first-order elimination to each course of each individualâ€™s MTX concentration time
data. Details of the clinical trials and the pharmacokinetic analysis are described in the below listed references.* Descriptive statistics of the estimated pharmacokinetic parameters: V (L/m^{2});
Ke (1/hrs); Kcp (1/hrs); and Kpc (1/hrs) along with clearance (CL=(50/3)*Ke*V, ml/min/m^{2}) are given in the table below each graph. Estimates of MTX exposure: Area under the concentration vs time curve from 0 to 72 hrs
(AUC, μM*hr); and end of infusion, 24 hr, and 44 hr concentrations (μM) were determined based on the model estimated concentrations for each course. Descriptive statistics of these parameters are given in the table below each graph.
The percentage of courses with a 44 hr concentration greater than 1.0 μM was determined using the model estimated 44 hr MTX concentration. The plot shows the median (black curve),
25^{th}-75^{th} percentile (blue shaded region), and 1^{st}-99^{th} percentile (grey shaded region) model estimated MTX concentration with respect to time.