0 �� 7.9 ng ml?1 (Equations 2] and 3]), significantly better than the baseline model (Equation 1]) (��OF > ?33, P = 9.2 �� 10?9). No influence of HSA using either linear more info or non-linear binding was observed (��OF> +26 compared with the baseline model) and Kd was much higher (4580 �� 144 ng ml?1). The interaction model (Equation 6] Appendix 1]) improved significantly the prediction of Cu compared with the model including non-linear binding to AGP solely (��OF = ?7) with a Kd for AGP and HSA of, respectively, 421 and 23 300 ng ml?1. Pharmacokinetic modelling Several models were then sequentially elaborated to describe the relationship between Cu and Ctot. The baseline model (Equation 1]) predicted a free fraction (Equation 1]) of 3.5% with a small non-significant inter-patient variability of 11%.

Allowing for a correlation between the residual errors for Cu and Ctot resulted in a marked improvement of the model fit (��OF = ?68.7, P = 1.1 �� 10?16), The predictions of Cu based on our previous non-linear model (Equation 3]) [17], using a fixed Kd of 90 ng ml?1, are presented in Figure 2A. This model was not able to predict imatinib free concentrations observed in our population, yielding a major bias of ?70% (MPE range ?66/?71%), and a poor precision of 250%. A difference of about three-fold was apparent between measured and predicted free imatinib concentrations. Refinement of the model by allowing Kd to be estimated markedly improved the fit (��OF = ?166, P = 5.5 �� 10?38), finally yielding a Kd of 319 ng ml?1. This model described the data much better that the one assuming a constant free fraction (Equation 1], ��OF = ?37.

7, P = 8.3 �� 10?10). This approach drastically decreased the bias (from ?70 to 4%, with 95% CI ?2, 10%) and improved the precision (43%) of the model, showing a good correlation between measured and estimated free imatinib concentrations (Figure 2B). A reduced model using a linear (Equation 2]) function of AGP described the data worse than the non-linear model (��OF = +12.9). The hyperbolic dependency of imatinib observed free fractions on plasma AGP concentrations depicted in Figure 3 is in accordance with this finding. Figure 2 (A)Individual predicted (predicted by Widmer et al. equation [17]) vs. measured free concentrations of imatinib. (B) Individual predictions (predicted by our final model, see text) vs. measured free imatinib concentrations. Anacetrapib The dotted line represents … Figure 3 Imatinibfree fractions vs.