The effect of age on the early disposition of doxorubicin

Abstract

Purpose

Clinical studies indicate that anthracycline cardiotoxicity increases with patient age. This may be due to altered pharmacokinetics or pharmacodynamics. A parameter termed 'early clearance' has been shown to decrease with age in patients receiving intravenous doxorubicin. This parameter, as defined, has no immediate relationship to any physiologically based pharmacokinetic parameter. We therefore reevaluated the pharmacokinetic data to better define the relationship between doxorubicin disposition and patient age.

Methods

Four studies provided a total of 56 patients with evaluable pharmacokinetics. The volume of the central compartment, V_c, the distribution clearance, CL_d, and total body clearance, CL, were determined for each patient and regressed against age. A physiologically based pharmacokinetic (PBPK) model for doxorubicin was also used to evaluate the effects of age on doxorubicin disposition. Published blood flows associated with various patient ages were used to simulate plasma and tissue doxorubicin concentrations. The relationship between CL_d and initial tumor regression was also evaluated.

Results

No correlation was found between V_c and age (P>0.05). A highly significant correlation was observed between CL_d and age (P<0.0005) and there was a mild but significant relationship between CL and age (P<0.01). Use of the PBPK model with different age-related blood flows yielded virtually identical parameter values to the clinical data analyzed. Furthermore, relative tissue AUCs simulated in old and young patients compared well with those reported for daunorubicin disposition in young and old rats. In addition, a linear relationship was observed between initial tumor regression and CL_d.

Conclusions

Initial concentrations of doxorubicin following intravenous administration are higher in the elderly due to a decrease in CL_d rather than in V_c. On the basis of simulations with the PBPK model, the reduced CL_d appears to be related to altered regional blood flows in the elderly, and such changes may be of clinical significance.

Appendix

The differential equations for the PBPK model of doxorubicin

For lung:

$$ \eqalign{ & V_{LU} {{dC_{LU} } \over {dt}} = D + Q_{LI} {{C_{LI} } \over {R_{LI} }} + Q_H {{C_H } \over {R_H }} + Q_K {{C_K } \over {R_K }} + Q_L {{C_L } \over {R_L }} + \cr & Q_A {{C_A } \over {R_A }} + Q_B {{C_B } \over {R_B }} - \left( {Q_{LI} + Q_H + Q_K + Q_L + Q_A + Q_B } \right){{C_{LU} } \over {R_{LU} }} \cr} $$

For plasma:

$$ V_P {{dC_P } \over {dt}} = \left( {Q_{LI} + Q_H + Q_K + Q_L + Q_A + Q_B } \right)\left( {{{C_{LU} } \over {R_{LU} }} - C_P } \right) $$

For liver:

$$ V_{LI} {{dC_{LI} } \over {dt}} = \left( {Q_{LI} - Q_G - Q_S } \right)\left( {C_P - {{C_{LI} } \over {R_{LI} }}} \right) + Q_G \left( {{{C_G } \over {R_G }} - {{C_{LI} } \over {R_{LI} }}} \right) + Q_S \left( {{{C_S } \over {R_S }} - {{C_{LI} } \over {R_{LI} }}} \right) - CL{{C_{LI} } \over {R_{LI} }} $$

For kidneys:

$$ V_K {{dC_K } \over {dt}} = Q_K \left( {C_P - {{C_K } \over {R_K }}} \right) $$

For lean tissue:

$$ V_L {{dC_L } \over {dt}} = Q_L \left( {C_P - {{C_L } \over {R_L }}} \right) $$

For adipose tissue:

$$ V_A {{dC_A } \over {dt}} = Q_A \left( {C_P - {{C_A } \over {R_A }}} \right) $$

For bone marrow:

$$ V_B {{dC_B } \over {dt}} = Q_B \left( {C_P - {{C_B } \over {R_B }}} \right) $$

For gastrointestinal tissue:

$$ V_G {{dC_G } \over {dt}} = Q_G \left( {C_P - {{C_G } \over {R_G }}} \right) $$

For spleen:

$$ V_S {{dC_S } \over {dt}} = Q_S \left( {C_P - {{C_S } \over {R_S }}} \right) $$

Nomenclature

D:

Dose for i.v. bolus administration, nanograms

C:

Concentration, nanograms per milliliter

CL:

Total body clearance, milliliters per minute

Q:

Plasma flow rate, milliliters per minute

R:

Tissue-to-plasma equilibrium distribution ratio for linear binding

V :

Volume, milliliters

Subscripts

G:

Gastrointestinal tissue

K:

Kidney

LI:

Liver

L:

Lean tissue

P:

Plasma

B:

Bone marrow

H:

Heart

A:

Adipose tissue

S:

Spleen

LU:

Lung