2). The Kd value was 4370 ng ml?1 (assuming two binding sites). The fit did not change assuming selleck one, two, three or four binding sites to this protein. No clear relationship was apparent between observed imatinib free fractions and plasma HSA concentrations (Figure 3). Interaction models assessing the simultaneous influence of linear binding to AGP and linear or non-linear binding to HSA (Equation 4] or Equation 5], Appendix 1]), did not fit the data as well as the non-linear AGP model solely (��OF < ?3.5, P = 0.06), whatever the number of binding sites assumed for HSA. Conversely, by using Equation 6] (non-linear AGP and linear HSA relationship) a statistical improvement of the model was observed (��OF < ?9.8, P = 1.7 �� 10?3). The Kd value for AGP was 411 �� 39.

1 ng ml?1 and for HSA was 22 300 �� 7850 ng ml?1 for two binding sites (no difference was observed considering one, two or three binding sites). The goodness-of-fit plots were, however, not better than the ones considering AGP only and showed similar non-significant bias (MPE 4%) and precision (MRSE 42%). The influence of HSA on the prediction of Cu was thus considered marginal and was not retained. The final results of the analyses of Ctot as a function of Cu and conversely are presented in Table 3. The model-based relationship between imatinib total and free concentrations based on the final relationship (Equation 3]) using a Kd of 319 ng ml?1 and a L of 11 700, stratified according to several levels of AGP concentrations, is presented in Figure 4. Figure 5 provides goodness-of-fit plots of observed vs.

predicted and individual predicted free imatinib concentrations from the final model. Figure 4 Imatinib total concentrations Ctot vs. predicted free concentrations based on the final model determined in this study, integrating AGP values of 0.5, 0.75, 1, 1.5 g l?1 and 2 g l?1 Figure 5 Goodness-of-fitplots of imatinib observed total concentrations (A and B) and unbound concentrations (C and D) vs. population predictions (A and C) and individual predictions (B and D) for the simultaneous fit Discussion This study allowed for the first time the full characterization of the pharmacokinetic profile of total and unbound imatinib concentrations and the description of the relationships governing the equilibrium between total and free imatinib concentrations.

The population pharmacokinetics of total imatinib concentrations could be adequately described using a one compartment model for total and unbound concentrations. The estimated values of CLtot and Vd,tot are in close accordance with our previous results and in good agreement with previously reported studies AV-951 [10, 30�C32]. Intersubject variabilities on CL and Vd were of the same magnitude for total and free concentrations, although poorly estimated.