Prediction of free imatinib concentrations based on total plasma concentrations in patients with gastrointestinal stromal tumours

Abstract

Aim: Total imatinib concentrations are currently measured for the therapeutic drug monitoring of imatinib, whereas only free drug equilibrates with cells for pharmacological action. Due to technical and cost limitations, routine measurement of free concentrations is generally not performed. In this study, free and total imatinib concentrations were measured to establish a model allowing the confident prediction of imatinib free concentrations based on total concentrations and plasma proteins measurements.

Methods: One hundred and fifty total and free plasma concentrations of imatinib were measured in 49 patients with gastrointestinal stromal tumours. A population pharmacokinetic model was built up to characterize mean total and free concentrations with inter-patient and intrapatient variability, while taking into account α1 -acid glycoprotein (AGP) and human serum albumin (HSA) concentrations, in addition to other demographic and environmental covariates.

Results: A one compartment model with first order absorption was used to characterize total and free imatinib concentrations. Only AGP influenced imatinib total clearance. Imatinib free concentrations were best predicted using a non-linear binding model to AGP, with a dissociation constant Kd of 319 ng ml(-1) , assuming a 1:1 molar binding ratio. The addition of HSA in the equation did not improve the prediction of imatinib unbound concentrations.

Conclusion: Although free concentration monitoring is probably more appropriate than total concentrations, it requires an additional ultrafiltration step and sensitive analytical technology, not always available in clinical laboratories. The model proposed might represent a convenient approach to estimate imatinib free concentrations. However, therapeutic ranges for free imatinib concentrations remain to be established before it enters into routine practice.

Figure 1

Total (black circles) and free (white circles) imatinib observed concentrations in patients scaled for 400 mg once daily imatinib, with the mean population prediction (solid line) and 95% prediction interval (dashed lines)

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. The dotted line represents a non-parametric local regression function while the black dotted line represents the identity line

Figure 3

Imatinibfree fractions vs. A) AGP and B) HSA plasma concentrations

Figure 4

Imatinib total concentrations C_tot 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