Introduction to taxane pharmacokinetics and pharmacodynamics

Abstract

Objective. To compare the pharmacokinetics and pharmacodynamics of the taxanes, paclitaxel and docetaxel.

Data sources. A MEDLINE search was conducted using docetaxel, dose, drug interactions, liver dysfunction, liver impairment, mechanism of action, paclitaxel, pharmacodynamics, pharmacokinetics, and schedule as search terms. Reference lists, bibliographies of pertinent articles, and abstracts from the American Society of Clinical Oncology and the American Association for Cancer Research annual meetings were also identified and reviewed. Both preclinical and clinical literature were reviewed and analyzed.

Data synthesis. The taxanes, paclitaxel and docetaxel, are a novel class of antineoplastic drugs that provide notable activity, and produce high response rates but minimal side effects. These agents share a similar mechanism of action, but several important pharmacokinetic and pharmacodynamic differences exist. The higher tubulin affinity, slower efflux from cells, triphasic elimination, and prolonged drug exposure of docetaxel confer pharmacokinetic and pharmacodynamic advantages over paclitaxel. The nonlinear pharmacokinetics of paclitaxel may result in disproportionate increases in plasma concentrations and AUCs; however, several safe and effective paclitaxel regimens are currently used. Because the taxanes are metabolized extensively in the liver by cytochrome P-450 enzymes, patients with hepatic impairment have reduced total body clearance that may result in increased toxicity. Additionally, drugs that induce, inhibit, or compete with microsomal enzymes known to metabolize the taxanes, can result in clinically significant drug interactions. These pharmacokinetic differences should be carefully considered when dosing and scheduling paclitaxel or docetaxel in clinical practice.