CLINICAL PHARMACOKINETICS OF PACLITAXEL

Paclitaxel is a new anticancer agent showing significant promise as th erapy for solid tumours and leukaemia, given alone or in combination w ith other chemotherapeutic agents. Paclitaxel concentrations in biolog ical specimens can be measured using high performance liquid chromatog raphy, or more recently by immunoassay. Pharmacokinetic studies in whi ch adults have been administered paclitaxel intravenously over 1 to 96 hours have demonstrated the following pharmacokinetic characteristics : extensive tissue distribution; high plasma protein binding (approxim ately 90 to 95%); variable systemic clearance, with average clearances ranging from 87 to 503 ml/min/m(2) (5.2 to 30.2 L/h/m(2)): and minima l renal excretion of parent drug (<10%). In vitro and in vivo studies have demonstrated that paclitaxel is extensively metabolised by the li ver to 3 primary metabolites. Cytochrome P450 enzymes of the CYP3A and CYP2C subfamilies appear to be involved in hepatic metabolism of pacl itaxel. Although early reports suggested that paclitaxel has first-ord er pharmacokinetics, some recent trials in children and adults suggest that its elimination is saturable. The clinical importance of saturab le elimination would be greatest when large dosages are administered a nd/or the drug is infused over a shorter period of time. In these situ ations, achievable plasma concentrations are likely to exceed the affi nity constant for elimination (K-m). Thus, small changes in dosage or infusion duration may result in disproportionately large alterations i n paclitaxel systemic exposure, potentially influencing patient respon se. A pharmacokinetic analysis of the combination of cisplatin and pac litaxel has demonstrated that paclitaxel clearance is apparently seque nce dependent. Patients administered cisplatin prior to paclitaxel had lower clearances and greater clinical toxicity than patients receivin g paclitaxel before cisplatin. Additional pharmacodynamic analyses hav e shown nonhaematological and haematological toxicity to correlate bet ter with parameters of paclitaxel exposure (e.g. area under the plasma concentration-time curve, duration of plasma concentrations exceeding 0.1 mu mol/L) than with the administered dosage.