Taxanes: An overview of the pharmacokinetics and pharmacodynamics

Paclitaxel and docetaxel have emerged in the last two decades as effective antitumor agents in a variety of malignancies. Paclitaxel is a semisyntheti c taxane isolated from bark of the Pacific yew tree. Docetaxel is a semisyn thetic taxane derived from the needles of the European yew (Taxus baccata). These compounds bind to tubulin, leading to microtubule stabilization, mit otic arrest and, subsequently, cell death. Plasma clearance of paclitaxel e xhibits nonlinear kinetics, which results in a disproportionate change in p lasma concentration and area under the curve (AUC) with dose alterations. I n contrast, docetaxel has a linear disposition over the dose ranges used cl inically, so its concentration changes linearly with changes in the dosage. Premedicating with corticosteroids and histamine H-1 and H-2 receptor anta gonists is advocated prior to paclitaxel administration; prior to docetaxel administration, premedication with corticosteroids is suggested. The taxan es are metabolized in the liver by the cytochrome P-450 enzymes and are eli minated in the bile. The known metabolites are either inactive or less pote nt than the parent compounds. The toxic effects associated with paclitaxel therapy are mainly neutropenia, peripheral neuropathy, and, rarely, cardiot oxicity. Docetaxel toxicity produces mainly myelosuppression and a cumulati ve dose fluid retention syndrome. Paclitaxel demonstrates sequence-dependen t interactions with cisplatin, cyclophosphamide, and doxorubicin. Docetaxel has shown increased myelosuppression with preceding ifosfamide in a prelim inary study. The future holds increasing, indications for taxanes in newer combination regimens; consideration of their pharmacologic characteristics is an important aspect of designing and applying new taxane-based treatment regimens. (C) 1999, Elsevier Science Inc.