Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein

Abstract

Aims: The aims of this observational study were to assess the variability in imatinib pharmacokinetics and to explore the relationship between its disposition and various biological covariates, especially plasma alpha1-acid glycoprotein concentrations.

Methods: A population pharmacokinetic analysis was performed using NONMEM based on 321 plasma samples from 59 patients with either chronic myeloid leukaemia or gastrointestinal stromal tumours. The influence of covariates on oral clearance and volume of distribution was examined. Furthermore, the in vivo intracellular pharmacokinetics of imatinib was explored in five patients.

Results: A one-compartment model with first-order absorption appropriately described the data, giving a mean (+/-SEM) oral clearance of 14.3 l h-1 (+/-1.0) and a volume of distribution of 347 l (+/-62). Oral clearance was influenced by body weight, age, sex and disease diagnosis. A large proportion of the interindividual variability (36% of clearance and 63% of volume of distribution) remained unexplained by these demographic covariates. Plasma alpha1-acid glycoprotein concentrations had a marked influence on total imatinib concentrations. Moreover, we observed an intra/extracellular ratio of 8, suggesting substantial uptake of the drug into the target cells.

Conclusion: Because of the high pharmacokinetic variability of imatinib and the reported relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be further investigated. Ideally, such an approach should take account of either circulating alpha1-acid glycoprotein concentrations or free imatinib concentrations.

Figure 4

Representation of the distribution of imatinib, based on concentrations and volumes (V_tot = Vd = total imatinib volume of distribution, V_AGP = total α₁-acid glycoprotein (AGP) plasma volume; V_u = free imatinib volume, C_tot = total imatinib concentration, C_u = free imatinib concentration, C_b = concentration of imatinib bound to AGP, AGP_tot = total AGP concentration, AGP_u = free AGP concentration, AGP_b = concentration of AGP bound to imatinib, L = scaling factor)

Figure 2

Pharmacokinetic parameters derived from the demographic covariates model (left panel) and from the final α₁-acid glycoprotein (AGP) model (right panel), plotted according to AGP plasma concentrations

Figure 1

Plasma imatinib concentrations observed in patients receiving imatinib, together with the mean population prediction (solid line) and 90% prediction interval (dashed lines). The graphs represent a once (upper part) or twice (lower part) daily regimen, based either on the demographic covariates model (left) or on the final α₁-acid glycoprotein (AGP) model (right) (values adjusted to 400 mg q.d.; AGP model curves generated assuming mean values of AGP level and f_u)

Figure 3

Intracellular and plasma pharmacokinetic profiles of imatinib in five individual patients (solid lines, plasma concentrations; broken lines, peripheral blood mononuclear cell concentrations)