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Clinical Pharmacokinetics of Paclitaxel

Authors: Daryl Sonnichsen; Daryl Sonnichsen; Mary V. Relling; Mary V. Relling;

Clinical Pharmacokinetics of Paclitaxel

Abstract

Paclitaxel is a new anticancer agent showing significant promise as therapy for solid tumours and leukaemia, given alone or in combination with other chemotherapeutic agents. Paclitaxel concentrations in biological specimens can be measured using high performance liquid chromatography, or more recently by immunoassay. Pharmacokinetic studies in which adults have been administered pacliaxel intravenously over 1 to 96 hours have demonstrated the following pharmacokinetic characteristics: extensive tissue distribution; high plasma protein binding (approximately 90 to 95%); variable systemic clearance, with average clearances ranging from 87 to 503 ml/min/m2 (5.2 to 30.2 L/h/m2); and minimal renal excretion of parent drug (< 10%). In vitro and in vivo studies have demonstrated that paclitaxel is extensively metabolised by the liver to 3 primary metabolites. Cytochrome P450 enzymes of the CYP3A and CYP2C subfamilies appear to be involved in hepatic metabolism of paclitaxel. Although early reports suggested that paclitaxel has first-order pharmacokinetics, some recent trials in children and adults suggest that its elimination is saturable. The clinical importance of saturable elimination would be greatest when large dosages are administered and/or the drug is infused over a shorter period of time. In these situations, achievable plasma concentrations are likely to exceed the affinity constant for elimination (Km). Thus, small changes in dosage or infusion duration may result in disproportionately large alterations in paclitaxel systemic exposure, potentially influencing patient response. A pharmacokinetic analysis of the combination of cisplatin and paclitaxel has demonstrated that paclitaxel clearance is apparently sequence dependent. Patients administered cisplatin prior to paclitaxel had lower clearances and greater clinical toxicity than patients receiving paclitaxel before cisplatin. Additional pharmacodynamic analyses have shown nonhaematological and haematological toxicity to correlate better with parameters of paclitaxel exposure (e.g. area under the plasma concentration-time curve, duration of plasma concentrations exceeding 0.1 mumol/L) than with the administered dosage.

Keywords

Adult, Dosage Forms, Immunoassay, Paclitaxel, Drug Administration Routes, Blood Proteins, Absorption, Child, Preschool, Humans, Drug Therapy, Combination, Tissue Distribution, Child, Chromatography, High Pressure Liquid, Protein Binding

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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
158
Top 10%
Top 1%
Top 10%
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