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.
Pharmacokinetics and pharmacodynamics of combination chemotherapy with paclitaxel and epirubicin in breast cancer patients / Danesi, R; Innocenti, F; Fogli, S; Gennari, A; Baldini, E; Di Paolo, A; Salvadori, B; Bocci, G; Conte, Pierfranco; Del Tacca, M.. - In: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY. - ISSN 0306-5251. - STAMPA. - 53:5(2002), pp. 508-518. [10.1046/j.1365-2125.2002.01579.x]
Pharmacokinetics and pharmacodynamics of combination chemotherapy with paclitaxel and epirubicin in breast cancer patients
CONTE, Pierfranco;
2002
Abstract
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.File | Dimensione | Formato | |
---|---|---|---|
Brit J Clinical Pharma - 2002 - Danesi - Pharmacokinetics and pharmacodynamics of combination chemotherapy with paclitaxel.pdf
Open access
Tipologia:
Versione pubblicata dall'editore
Dimensione
176.35 kB
Formato
Adobe PDF
|
176.35 kB | Adobe PDF | Visualizza/Apri |
Pubblicazioni consigliate
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris