Elsevier

Urology

Volume 54, Issue 6, Supplement 1, December 1999, Pages 22-29
Urology

Original Articles
Taxanes: an overview of the pharmacokinetics and pharmacodynamics

https://doi.org/10.1016/S0090-4295(99)00451-3Get rights and content

Abstract

Paclitaxel and docetaxel have emerged in the last two decades as effective antitumor agents in a variety of malignancies. Paclitaxel is a semisynthetic taxane isolated from bark of the Pacific yew tree. Docetaxel is a semisynthetic taxane derived from the needles of the European yew (Taxus baccata). These compounds bind to tubulin, leading to microtubule stabilization, mitotic arrest and, subsequently, cell death. Plasma clearance of paclitaxel exhibits nonlinear kinetics, which results in a disproportionate change in plasma concentration and area under the curve (AUC) with dose alterations. In contrast, docetaxel has a linear disposition over the dose ranges used clinically, so its concentration changes linearly with changes in the dosage. Premedicating with corticosteroids and histamine H1 and H2 receptor antagonists is advocated prior to paclitaxel administration; prior to docetaxel administration, premedication with corticosteroids is suggested. The taxanes are metabolized in the liver by the cytochrome P-450 enzymes and are eliminated in the bile. The known metabolites are either inactive or less potent than the parent compounds. The toxic effects associated with paclitaxel therapy are mainly neutropenia, peripheral neuropathy, and, rarely, cardiotoxicity. Docetaxel toxicity produces mainly myelosuppression and a cumulative dose fluid retention syndrome. Paclitaxel demonstrates sequence-dependent interactions with cisplatin, cyclophosphamide, and doxorubicin. Docetaxel has shown increased myelosuppression with preceding ifosfamide in a preliminary 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.

Section snippets

Structure and mechanism of action

The taxane class of compounds (Figure 1) is composed of a taxane ring with a 4-member oxetan ring attached at positions C-4 and C-5, and a bulky ester side chain at C-13.1, 2, 3, 4 The configuration of this ester chain is essential for the antitumor activity.5 Docetaxel configuration differs structurally from paclitaxel in two ways: in the structure of the attachment to the C5′ carbonyl in the C-13 side chain; in the loss of the acetyl group esterified to the C-10 hydroxyl of the baccatin ring.5

Paclitaxel

Taxoid compounds are insoluble in aqueous solution. Paclitaxel is formulated in 50% alcohol and 50% polyoxyethylated castor oil derivative. After dilution into sodium chloride for injection, or 5% dextrose solution in glass containers, it is usually administered through specific in-line filters and tubing sets.16

The observation of hypersensitivity reactions to paclitaxel in early phase I trials led to prolonging the infusion time to either 6 or 24 hours. These reactions could be attributed to

Paclitaxel

The taxanes are highly bound to plasma protein (paclitaxel 95% bound, docetaxel >90%5). Tissue distribution and binding influence the rate of plasma clearance; paclitaxel shows saturable distribution and nonlinear disposition.6, 7, 8 An agent with nonlinear disposition lacks a proportional relationship between dose and the area under the plasma concentration of drug versus time curve, the so-called plasma AUC (Figure 2, curved line). This causes a disproportionate degree of change in AUC and

Metabolism

Taxane metabolism is primarily hepatic and renal clearance is minimal (<5% excretion in urine).25 Both taxanes are metabolized by hepatic cytochrome P450 enzyme systems and eliminated by biliary excretion.5, 26, 27, 28, 29 Paclitaxel undergoes stereospecific CYP2C8 hydroxylation at the C6′ position of the taxane nucleus to form 6-α-hydroxy-paclitaxel, the major metabolite (Figure 3). Interestingly, this biotransformation is inhibited by 0.1% v/v Cremophor El.29 Paclitaxel is also hydroxylated

Toxicity

Myelosuppression is the dose limiting toxicity of both taxanes. Pharmacology studies during clinical trials of paclitaxel have found that the severity of neutropenia is most closely associated with the duration that plasma levels remain above 50–100 nmol/L.34 Thus, the severity of the neutropenia is related to the infusion duration of paclitaxel; it increases with longer infusions. Mucositis follows the same pattern.5, 6, 7, 8 Docetaxel causes neutropenia equivalent to that with a 24-hour

Drug interactions

Cisplatin, when administered prior to paclitaxel, causes a significantly higher incidence of neutropenia as a result of a 25% reduction in paclitaxel clearance.37 Reversing the sequence appears to eliminate this detrimental effect. The combination of carboplatin and paclitaxel has emerged as safe and well tolerated. The severity of thrombocytopenia is less than that seen with the administration of carboplatin alone.38, 39 These findings may reflect differential effects of the platinum compounds

Conclusion

The two important members of the taxoid family—paclitaxel and docetaxel—are similar in their mechanism of action and wide spectrum of activity. However, there are subtle differences in toxicity profiles. The manifestation of fluid retention syndrome appears to be unique to docetaxel, whereas cardiotoxicity is a side effect observed with paclitaxel alone. The pharmacokinetics of the two taxanes are distinct in the clinical dosage range. Paclitaxel shows a nonlinear disposition, which has a major

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