A. Aldaz(1), L. ZufÃa(1), I. Aquerreta(1), A. Gúrpide(2), J. Giráldez(1).
(1) Pharmacy Department, (2) Oncology Department, University Hospital of Navarra
The paclitaxel disposition is nonlinear and hepatic metabolism and biliary excretion have important roles. The influence of hepatic dysfunction on the pharmacokinetics and toxicities of the drug are not enough known. Some patients with hepatic metastases and/or elevated transaminase levels have been reported to have had increased toxicity and altered paclitaxel pharmacokinetics and there is limited data about the disposition of this drug in hepatic transplant recipients. Because paclitaxel has potential clinical utility for the treatment ot several tumours, it was believed necessary to formally define paclitaxel dosification in this last population
Objectives: The aim of this study is to analize the paclitaxel disposition in liver transplantation patients to optimize therapy and avoid infra and/or supradosification affecting the efficacy and toxicity of the treatment.
Patients and methods: Paclitaxel pharmacokinetic parameters of lung cancer patients (two men and a woman) with liver transplantation were estimated. All three patients received paclitaxel as a three hours intravenous infusion and carboplatin chemotherapy according to the protocol developed by the Oncology Department of the University Hospital of Navarra [ 1] . Blood samples were collected into heparinized glass tubes (Venoject) at different times during the first cycle of their corresponding treatment and were analyzed according to a high performance liquid chromatography (HPLC) method developed and validated by the pharmacokinetic laboratory of the Pharmacy Department at the University Hospital of Navarra. Paclitaxel pharmacokinetic parameters was carried out by noncompartimental analysis using software WinNonLin 3.0 (Scientific Consultants, NC, USA).
Results: The pharmacokinetic parameters obtained in this study were similar to the median values (range 17.4-22.8 L/h*m2) found by other researchers for patients with normal hepatic biochemistry [ 2-4] . Only the woman with elevated transaminase levels showed a total clearance lower (15.02 L/h*m2 versus 18.04 L/h*m2). For hepatically metabolised drugs, those that are metabolised by CYP3A4 appear to be eliminated faster in women [ 5] ; so, in our experience, the lower value of clearance for the woman emphasaze the effect of hepatic injury in the paclitaxel clearence.
Conclusion: Our results show that paclitaxel pharmacokinetic behavior in liver transplantation patients is similar to the control population with normal hepatic biochemistry test, so these cancer patients could receive paclitaxel with no recommendations on dosage reductions.
References:
[ 1] L. ZufÃa, A. Aldaz, J.M. AramendÃa et al. Determination of docetaxel and paclitaxel in human plasma by high-performance liquid chromatography. Validation and application to clinical pharmacokinetic studies. (Enviado al Ther. Drug Monit.)
[ 2] C.H. Smorenburg, A.J. Ten Tije, J. Verweij et al. Altered clearance of unbound paclitaxel in elderly patients with metastatic breast cancer. Eur. J. Cancer. 2004; 39: 196-202.
[ 3] K. Mross, B. Häring, N. Holländer et al. Comparison of 1-hour and 3-hours paclitaxel infusion pharmacokinetics: result from a randomized trial. Oncologie 2002; 25: 503-508.
[ 4] M.T. Huizing, C.F. Keung, H. Rosing et al. Pharmacokinetics of paclitaxel study in platinum-pretreated ovarian cancer patients. J. Clin. Oncol. 1993, 11(1): 2127-2135.
[ 5] M Gandhi, F. Aweeka, R.M. Greenblatt et al. Sex differences in pharmacokinetics and pharmacodynamics. Annu. Rev. Pharmacol. Toxicol. 2004; 44: 499-523.
Reference: PAGE 14 (2005) Abstr 824 [www.page-meeting.org/?abstract=824]
Poster: poster