Feasibility study and pharmacokinetics of low-dose paclitaxel in cancer patients with severe hepatic dysfunction

Abstract

The aim of this study is to investigate the feasibility and determine the pharmacokinetics of low-dose paclitaxel in cancer patients with severe hepatic dysfunction. This was a prospective study. Patients with liver metastases who had either transaminase serum levels higher than 10 times the upper normal limit or bilirubin serum levels higher than 5 times the upper normal limit were eligible. All patients underwent pharmacokinetic evaluation during the first course of treatment. Pharmacokinetics in severe hepatic dysfunction patients were compared with data from a reference group of patients with normal hepatic function who participated in a phase I study. Nine severe hepatic dysfunction patients were treated with paclitaxel 70 mg/m administered as a 1-h infusion every 2 weeks. They received a median three treatment courses (range 1-9) without clinically relevant toxicity. The area under the concentration-time curve of paclitaxel was markedly higher in severe hepatic dysfunction patients when compared with the normal hepatic function control group treated with the same dose (98% increase, P<0.001). Area under the concentration-time curve and the time above 0.1 micromol/l (T>0.1) concentration threshold in the severe hepatic dysfunction patients who received paclitaxel 70 mg/m approximated pharmacokinetics of paclitaxel in patients with normal liver function who received 130 mg/m. Maximum plasma concentration (Cmax) did not differ between the two groups. In conclusion, paclitaxel 70 mg/m was safely delivered every 2 weeks in patients with severe hepatic dysfunction and resulted in adequate plasma concentrations. Paclitaxel at this dosage can be taken as an option for severe hepatic dysfunction patients who are expected to get clinical benefits from taxanes.

Patients with Advanced Pancreatic Cancer and Hyperbilirubinaemia: Review and German Expert Opinion on Treatment with nab-Paclitaxel plus Gemcitabine

“…A pharmacokinetic-pharmacodynamic model, derived from one of the mentioned studies in 35 patients with solid tumours receiving paclitaxel monotherapy, predicted the following recommendation for the initial paclitaxel dose based on the total bilirubin level: ≤ 1.25 × ULN: 175 mg/m 2 (100% dose), 1.26-2.0 × ULN: 115 mg/m 2 (66%), 2.1-3.5 × ULN: 100 mg/m 2 (57%) and 3.6-10 × ULN: 70 mg/m 2 (40%) [48]. The validity of the recommendation for an initial paclitaxel dose of 40% was confirmed in a pharmacokinetic study in 9 patients with severe hepatic dysfunction caused by liver metastases and a bilirubin level of 3-11 × ULN: Treatment with 70 mg/m 2 paclitaxel was safe and led to adequate plasma concentrations [51]. …”

Weekly paclitaxel in escalating doses in a patient with anthracycline-resistant, triple-negative, metastatic breast cancer with severe liver dysfunction

“…[4] Another such study recommended the dose of 70 mg/ m 2 every 2 weeks. [5] Huizing and colleagues studied nine patients with advanced breast cancer receiving paclitaxel 250 mg/ m 2 as a 3-h infusion with subsequent granulocyte–colony stimulating factor support. Two patients with liver function disturbances showed a tendency to higher paclitaxel and 6-alfa hydroxypaclitaxel AUC levels, with more pronounced neuropathy.…”

“…Studies of paclitaxel pharmacokinetics in patients with normal or mildly impaired liver function suggested a negative correlation between total bilirubin concentrations and paclitaxel elimination. [1][2][3][4][5][6] Venook et al described higher hematological toxicities in patients with liver dysfunction receiving paclitaxel every 3-weekly over 24 h and over 3 h, and suggested dose reductions as a means of overcoming this toxicity. [2] Wilson et al, in a combined Phase I/II study, studied the pharmacokinetics involved in a 96-h infusion of paclitaxel and found correlations between tumor involvement of the liver, aspartate aminotransferase and total bilirubin concentrations and reduced paclitaxel clearance in patients with advanced breast cancer.…”

“…Weekly paclitaxel has not been studied in the setting of severe liver dysfunction. [1][2][3][4][5][6] We present the report of one such case who had a gratifying response to escalating doses of weekly paclitaxel thus suggesting that patients with severe liver dysfunction can derive benefits from such a strategy.…”

“…Administration of paclitaxel is contraindicated once the liver functions are more than 10-times the upper limit of normal (>10 ULN). [1][2][3][4][5][6] Serious toxicity can be seen even with lesser degrees of liver dysfunction. Weekly paclitaxel has not been studied in the setting of severe liver dysfunction.…”