Influence of the interval between the administration of doxorubicin and paclitaxel on the pharmacokinetics of these drugs in patients with locally advanced breast cancer

Citation
A. Moreira et al., Influence of the interval between the administration of doxorubicin and paclitaxel on the pharmacokinetics of these drugs in patients with locally advanced breast cancer, CANC CHEMOT, 48(4), 2001, pp. 333-337
Citations number
12
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER CHEMOTHERAPY AND PHARMACOLOGY
ISSN journal
0344-5704 → ACNP
Volume
48
Issue
4
Year of publication
2001
Pages
333 - 337
Database
ISI
SICI code
0344-5704(200110)48:4<333:IOTIBT>2.0.ZU;2-V
Abstract
Purpose: The combination of bolus doxorubicin followed by a 3-h infusion of paclitaxel has high antitumor activity in patients with metastatic breast cancer, but is limited by unexpected cardiac toxicity. In contrast, the adm inistration of the two drugs 16 li apart has similar antitumor activity but less cardiac toxicity. The purpose of this study was to compare the pharma cokinetics of these drugs when doxorubicin administration preceded paclitax el by 30 min or by 24 h. Patients and methods: Women with locally advanced 2 breast cancer were treated with doxorubicin (60 mg/m(2) i.v. bolus) follo wed 24 h later by paclitaxel (200 mg/m(2) i.v. over 3 h) for six cycles (fo ur before and two after surgery). In one of the first two cycles doxorubici n preceded paclitaxel by 30 min instead of 24 h, with plasma sampling for p harmacokinetic analysis up to 48 h. Determination of drug levels in plasma was done by HPLC. Results: A total of 28 patients were included. No clinica l cardiac toxicity was observed but five patients discontinued doxorubicin- paclitaxel treatment after four cycles because of a decrease in LVEF of at least 15% from baseline or to less than 50%. While paclitaxel pharmacokinet ics were not changed, there was a 30% and an 80% increase in the AUC(0-24h) for doxorubicin and doxorubicinol., respectively, when the drugs were admi nistered 30 min instead of 24 h apart. Even when paclitaxel was given 24 It after doxorubicin, there was a rebound 24% increase in the plasma concentr ation of doxorubicinol. Conclusions: Paclitaxel interferes with the pharmac okinetics of doxorubicin leading to higher systemic exposure to both doxoru bicin and doxorubicinol, which is more evident when the plasma concentratio n or the anthracyclines is higher. This interference may explain the higher incidence of cardiac toxicity observed when the two drugs are administered within a short interval.