Inverse relationship between leukaemic cell burden and plasma concentrations of daunorubicin in patients with acute myeloid leukaemia

Abstract

Aims: It has been shown that the cellular uptake and cytotoxicity of anthracyclines decrease with increasing cell density in vitro, an event termed 'the inocculum effect'. It is not known whether such an effect occurs in vivo. In this study the relationships between white blood cell (WBC) count, plasma and cellular concentrations of daunorubicin (DNR) in patients with acute myeloid leukaemia were investigated.

Methods: Plasma and mononuclear blood cells were isolated from peripheral blood from 40 patients with acute myeloid leukaemia at end of infusion (time 1 h), 5 and 24 h following the first DNR infusion. DNR concentrations were determined by high-pressure liquid chromatography and related to the WBC count at diagnosis. A population pharmacokinetic model was used to estimate the correlations between baseline WBC count, volume of distribution and clearance of DNR.

Results: A clear but weak inverse relationship between the baseline WBC count and plasma concentrations of DNR (r(2)=0.11, P<0.05) at time 1 was found. Furthermore, a clear relationship between baseline WBC count and DNR central volume of distribution using population pharmacokinetic modelling (dOFV 4.77, P<0.05) was also noted. Analysis of plasma DNR and the metabolite daunorubicinol (DOL) concentrations in patients with a high WBC count support that the low DNR/DOL concentrations are due a distribution effect.

Conclusion: This study shows that the leukaemic cell burden influences the plasma concentrations of anthracyclines. Further studies are needed to explore if patients with high a WBC count may require higher doses of anthracyclines.

Figure 1

Plasma daunorubicin (DNR) concentrations in relation to white blood cell (WBC) count in acute myeloid leukaemia patients (n = 40) directly after a 1-h DNR infusion. The dotted lines represent the 95% confidence limits

Figure 2

Plasma concentration of daunorubicin (DNR) in relation to plasma concentration of daunorubicinol (DOL) in acute myeloid leukaemia patients (n = 40) directly after a 1-h DNR infusion. The dotted lines represent the 95% confidence limits

Figure 3

Intracellular concentration of daunorubicin (DNR) in relation to white blood cell (WBC) count in acute myeloid leukaemia patients (n = 24) directly after a 1-h DNR infusion

Figure 4

Visual predictive checks (80% prediction interval) based on the population pharmacokinetic model by Callies et al. superimposed on the observed DNR and DOL plasma concentrations. Observed data (dots) and the 95% confidence intervals around the simulated median (dark grey), 10th and 90th percentiles (light grey) are shown. Solid and dotted lines are the corresponding median and percentiles, respectively, of the observed data

Figure 5

Visual predictive checks (80% prediction interval) for (A) the basic population pharmacokinetic (PK) model of daunorubicin (DNR) in plasma and (B) for the model including white blood cell (WBC) counts. Observed data (dots) and the 95% confidence intervals around the simulated median (dark grey), 10th and 90th percentiles (light grey) are shown. Solid and dotted lines are the corresponding median and percentiles, respectively, of the observed data