Paclitaxel dosage

L. K. Shao and D. C. Locke, Determination of Paclitaxel and related taxanes in bulk drug and injectable dosage forms by reversed phase liquid chromatography. Anal. Chem. 69 (1997), 2008-2016. 

Hypersensitivity reactions can occur due to the presence of contaminants or excipients in pharmaceutical dosage forms (e.g., outbreaks of eosinophilia-myalgia syndrome associated with oral tryptophan contaminants in various drugs). Another example is the anaphylactoid reactions to the surfactant Cremaophor EL, which is used in paclitaxel (Taxol). 

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 (10). A dosage reduction of 50% has been suggested in patients with moderate or severe hyperbilirubinemia or increased serum transaminases (4). 

In several studies, intravenous amifostine (910 mg/m ) preserved glomerular filtration rate when it was co-administered with cisplatin-containing regimens (213). Even after two cycles containing intravenous cisplatin 50 mg/m plus intravenous ifosfamide and etoposide or paclitaxel, glomerular filtration rate can fall by more than 30%, but concomitant use of amifostine prevented this. Even lower dosages of intravenous amifostine (for example 740 mg/m ) may be effective (220,221). 

The UK manufacturer of aprepitant recommends caution when it is used with antineoplastics that are metabolised by CYP3A4, particularly irinotecan, because of the possibility of increased toxicity with this drug. They also mention that etoposide, vinoreibine, docetaxel, paclitaxel, ifosfamide, imatinib, vinblastine and vincristine, were given without dosage adjustment for potential interactions, but as this was not a formal interaction study they recommend caution. However, with intravenous docetaxel, it appears that no important changes in pharmacokinetics occur, and therefore dosage adjustments are unlikely to be needed for this drug,... 

Based on a study in 35 patients with moderate to severe liver dysfunction treated with paclitaxel monotherapy given over 3 hours, recommendations on dosage adjustments, based on total bilirubin, have been proposed, as outlined in Table 1. 

Table 1 Proposed dosage adjustments for paclitaxel in liver impairment...

A pre-existing neuropathy as a result of prior therapy is not a contraindication to paclitaxel, but in severe cases of peripheral neuropathy a dosage reduction of 20% is recommended for subsequent courses. 

The duration of neutropenia is usually brief, and treatment delays for unresolved adverse hematological reactions on day 21 are rare. Paclitaxel-induced neutropenia does not always lead to infectious complications, and therefore a dosage reduction for... 

Pharmacokinetics The apparent volume of distribution and clearance of albumin-bound paclitaxel are significantly higher than Cremophor-based paclitaxel, in both animals and humans [94 ]. Albumin-bound paclitaxel has linear pharmacokinetics over a dosage range of 135-300 mg/rr [95 ]. The half-life is 22 hours, which is similar to that of Cremophor-based paclitaxel [96 ]. 

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