Paclitaxel

Mechanism of action

Paclitaxel acts by enhancing microtubule assembly and stabilizing microtubules [ , ]. Microtubules consist of polymers of tubulin in dynamic equilibrium with tubulin heterodimers. Their principal function is the formation of the mitotic spindle during cell division, but they are also active in many interphase functions, such as cellular motility, intracellular transport, and signal transmission. Paclitaxel inhibits the depolymerization of tubulin, and the microtubules formed in the presence of paclitaxel are extremely stable and dysfunctional. This stabilization impairs the essential assembly and disassembly required for dynamic cellular processes, and death of the cell results through disruption of the normal microtubular dynamics required for interphase processes and cell division. In tumor cells, cytotoxicity is represented by the appearance of abnormal microtubular bundles, which accumulate during G2 and mitosis, blocking the cell cycle [ ].

Pharmacokinetics

Paclitaxel has non-linear kinetics: peak plasma concentrations and drug exposure increase disproportionately with increasing doses and the pharmacokinetics depend on the schedule of administration. Saturation is reached with high-dose short infusions [ ]. Paclitaxel has been reported to follow both biphasic [ ] and triphasic models [ ]. The half-life has been estimated at 6–13 hours after intravenous administration [ ].

After intravenous administration, paclitaxel is extensively distributed, despite extensive binding to plasma proteins (89%), presumably albumin [ ]. Its routes of elimination have not been fully elucidated, but renal clearance accounts for an insignificant proportion of total systemic clearance, suggesting that metabolism, biliary excretion, or excretion via other routes are responsible for elimination [ ]. High concentrations of paclitaxel and its hydroxylated metabolites have been found in rat and human bile, suggesting hepatic metabolism [ ]. In all, 11 metabolites of paclitaxel have been identified, and paclitaxel metabolism to 6-α-hydroxypaclitaxel is an important detoxification pathway [ , ].

The effects of renal and hepatic dysfunction on paclitaxel elimination have not been studied extensively. Since renal clearance accounts for a small proportion of total clearance, dosage modifications are not considered necessary in patients with renal dysfunction.

One study has shown that patients with existing liver dysfunction have a reduced total body clearance of paclitaxel and require dosage reductions [ ]. A dosage reduction of 50% has been suggested in patients with moderate or severe hyperbilirubinemia or increased serum aminotransferases [ ].

Paclitaxel is formulated in a mixture of ethanol and Cremophor EL (polyethoxylated castor oil). Cremophor reduced the electrophoretic mobility of serum lipoproteins along with the appearance of a lipoprotein dissociation product. After serum was exposed to Cremophor in vitro or in vivo there was substantial binding of paclitaxel to the lipoprotein dissociation product(s), and this could represent an important factor in the distribution of paclitaxel [ ].

General adverse effects and adverse reactions

A summary of the incidences of the adverse effects of paclitaxel and adverse reactions to it in single-agent studies in 402 patients is given in Table 1 [ ].

Observational studies

In a single-center study of drug-eluting stents in 64 patients, paclitaxel-eluting stents in seven and sirolimus-eluting stents were used in 57 [ ]. There was procedural success in 63 patients. One 87-year-old patient died in hospital due to papillary muscle rupture and refractory heart failure. There were no 30-day cases of stent thrombosis, reinfarction, or target vessel reintervention. During follow-up one patient died in a rehabilitation facility 52 days after intervention due to nosocomial pneumonia and sepsis. There were no late cases of stent thrombosis, reinfarction, or target vessel re-intervention.

Cardiovascular

Paclitaxel causes disturbances in cardiac rhythm, but the relevance of these has not been fully elucidated. Originally, all patients in trials of paclitaxel were under continuous cardiac monitoring, owing to the risk of hypersensitivity reactions, and cardiac disturbances were therefore more likely to be detected. Many trials limited eligibility to patients without a history of cardiac abnormalities and to those who were not taking medications likely to alter cardiac conduction. The incidence of cardiac dysrhythmias in the population under study not treated with paclitaxel is unknown, and it is therefore not always possible to attribute dysrhythmias to paclitaxel in these patients. The Cremophor EL vehicle does not appear to be implicated in the incidence of dysrhythmias, although hypotension associated with hypersensitivity reactions may occur [ ].

The most common adverse cardiac effect of paclitaxel is asymptomatic bradycardia, which occurred in 29% of patients in one phase II trial [ ] and in 9% of patients in a further assessment of 402 patients in phase II trials [ ]. One phase I trial showed no significant cardiac dysrhythmias [ ], while another reported cardiac toxicity in 14% of patients, 74% of these being due to asymptomatic bradycardia [ ]. Bradycardia is not an indication for discontinuation of treatment, unless it is associated with atrioventricular conduction disturbances or clinically significant effects (for example symptomatic hypotension). More significant bradydysrhythmias and atrioventricular conduction disturbances have been reported during clinical trials, including Mobitz type I (Wenckebach syndrome) and Mobitz type II atrioventricular block [ , ].

One patient died in heart failure 7 days after receiving paclitaxel by infusion; this patient had no prior history of cardiac problems, apart from mild hypertension [ ].

The authors of a review of the cardiac toxicity associated with paclitaxel in a number of studies concluded that the overall incidence of serious cardiac events is low (0.1%) [ ]. Heart block and conduction abnormalities occurred infrequently and were often asymptomatic. Sinus bradycardia was the most frequent, occurring in 30% of patients. The causal relation of paclitaxel to atrial and ventricular dysrhythmias and cardiac ischemia was not entirely clear. There did not appear to be any evidence of cumulative toxicity or augmentation of acute cardiac effects of the anthracyclines.

In an attempt to clarify further the cardiotoxicity of paclitaxel, its effect on cardiovascular autonomic regulation has been investigated in 14 women [ ]. The authors concluded that autonomic modulation of heart rate is impaired by paclitaxel, but they were unable to say whether it would return to normal on withdrawal. They also investigated the effect of docetaxel on neural cardiovascular regulation in women with breast cancer, previously treated with anthracyclines [ ]. They concluded that docetaxel did not impair vagal cardiac control. The changes that they observed in blood pressure suggest that docetaxel changes sympathetic vascular control, although these changes seemed to be related to altered cardiovascular homeostasis rather than peripheral sympathetic neuropathy.

Continuous cardiac monitoring is recommended for patients with serious conduction abnormalities; however, routine cardiac monitoring is considered unnecessary in patients without a history of cardiac conduction abnormalities [ ]. Further studies are needed to determine the risk in patients treated with paclitaxel with predisposing cardiac risk factors.