Pharmacokinetics and pharmacodynamics of combination chemotherapy with paclitaxel and epirubicin in breast cancer patients

Abstract

Aims: To investigate the pharmacokinetics and pharmacodynamics of epirubicin and paclitaxel in combination, as well as the effects of paclitaxel and its vehicle Cremophor EL on epirubicin metabolism.

Methods: Twenty-seven female patients with metastatic breast cancer received epirubicin 90 mg m-2 i.v. followed 15 min or 30 h later by a 3 h i.v. infusion of paclitaxel 175, 200 and 225 mg m-2. Plasma concentrations of paclitaxel, epirubicin and epirubicinol were measured and the relationship between neutropenia and drug pharmacokinetics was evaluated using a sigmoid maximum effect (Emax) model. Finally, the influence of paclitaxel and Cremophor EL on epirubicin metabolism by whole blood was examined.

Results: An increase in epirubicinol plasma concentrations occurred after the start of the paclitaxel infusion, resulting in a significant increase in the area under the plasma concentration-time curve (AUC) of epirubicinol (+0.5 micromol l-1 h [95% CI for the difference: 0.29, 0.71],+0.66 micromol l-1 h [95% CI for the difference: 0.47, 0.85] and +0.82 micromol l-1 h [95% CI for the difference: 0.53, 1.11] at paclitaxel doses of 175, 200 and 225 mg m-2, respectively), compared with epirubicin followed by paclitaxel 30 h later (0.61+/-0.1 micromol l-1 h). A significant increase in epirubicin AUC (+0.74 micromol l-1 h [95% CI for the difference: 0.14, 1.34] and +1.09 micromol l-1 h [95% CI for the difference: 0.44, 1.74]) and decrease in drug clearance (CLTB) (-25.35 l h-1 m-2[95% CI for the difference: -50.18, -0.52] and -35.9 l h-1 m-2[95% CI for the difference -63,4,-8,36]) occurred in combination with paclitaxel 200 and 225 mg m-2 with respect to the AUC (3.16+/-0.6 micromol l-1 h) and CLTB (74.4+/-28.4 l h-1 m-2) of epirubicin followed by paclitaxel 30 h later. An Emax relationship was observed between neutropaenia and the time over which paclitaxel plasma concentrations were equal to or greater than 0.1 micromol l-1 (tC0.1). The tC0.1 value predicted to yield a 50% decrease in neutrophil count was 7.7 h. Finally, Cremophor EL markedly inhibited the metabolism of epirubicin to epirubicinol in whole blood.

Conclusions: Paclitaxel/Cremophor EL affects the disposition of epirubicinol and epirubicin. Furthermore, the slope factor of the Emax relationship between neutropenia and tC0.1 of paclitaxel suggests that the drugs might also interact at the pharmacodynamic level.

Figure 1

Plasma concentration vs time curves for paclitaxel 175 (▿), 200 (□) and 225 (•) mg m⁻² i.v. Symbols: mean values; vertical bars, s.d.

Figure 2

Scatter plots of individual values of C_max (a) and AUC (b) after increasing doses of paclitaxel in 21 subjects. The dotted line links the observed mean values (horizontal bars) of C_max and AUC, while the solid line intersects the theoretical mean values if C_max and AUC increased proportionally with dose.

Figure 3

Plasma concentration vs time curves of epirubicin 90 mg m⁻² i.v. administered alone (♦) or followed 15 min later by paclitaxel 175 (▿), 200 (□) and 225 (•) mg m⁻² i.v. Symbols: mean values; vertical bars, s.d.

Figure 4

Plasma concentration vs time curves for epirubicinol in patients given epirubicin 90 mg m⁻² i.v. administered alone (♦) or followed 15 min later by paclitaxel 175 (▿), 200 (□) and 225 (•) mg m⁻² i.v. Symbols: mean values; vertical bars, s.d.

Figure 5

Effect of paclitaxel (2.5 (▿) and 5 (▾) µmol l⁻¹) or Cremophor EL (2.5 (⋄) and 5 (♦) ml l⁻¹) on the production of epirubicinol by whole blood containing epirubicin 0.2 µmol l⁻¹. • epirubicin. Symbols: mean values; vertical bars, standard deviation of the mean. *P<0.05.

Figure 6

Pharmacokinetic–pharmacodynamic correlation between the percent decrease in absolute neutrophil count and tC_0.1 of paclitaxel in patients treated with epirubicin and paclitaxel. The solid line indicate the best fit of a sigmoid E_max pharmacodynamic model to the data.