Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients

Abstract

Paclitaxel (Taxol) is a potent anticancer drug with proven activity against a number of human solid tumours, including ovarian and breast, non-small-cell lung, and head and neck cancer (Huizing et al, 1995a;Rowinsky et al, 1995). Because of its poor water solubility the drug is formulated in a mixture of polyoxyethyleneglycerol triricinoleate 35 (Cremophor EL) and dehydrated ethanol USP (1:1, v/v; Taxol®). Prior to intravenous (i.v.) administration the drug solution is diluted 5-to 20-fold with saline or 5% dextrose. Patients receiving therapeutic dosages (e.g. 175 mg m -2 ) of paclitaxel (Taxol) receive about 25 ml of Cremophor EL solvent. The non-linear pharmacokinetic behaviour of paclitaxel in patients has been well documented (Huizing et al, 1993;Sonnichsen et al, 1994;Gianni et al, 1995;Kearns et al, 1995;Huizing et al, 1997). Both a reduction in the clearance and an over proportional increase in peak plasma concentration (C max ) of paclitaxel are observed with increasing dosages indicative that both drug elimination and distribution were affected. We have recently shown that the non-linear pharmacokinetics of paclitaxel in mice results from Cremophor EL exclusively, since linear plasma pharmacokinetics occurred when the same dose levels of paclitaxel were administered in a Cremophor EL free drug formulation (Sparreboom et al, 1996b). In patients, administration of paclitaxel in a Cremophor EL free formulation to test if the pharmacokinetics becomes linear is not a feasible option. Indirectly, however, our observations support the idea that Cremophor EL may also be responsible for the non-linear pharmacokinetics in patients provided that the plasma levels of Cremophor EL are in the same range as those observed in mice.In mice, the plasma concentrations of Cremophor EL as established by high-performance liquid chromatography (HPLC) ranged from 0.3 to 2.1% (Sparreboom et al, 1996b). Information on the pharmacokinetics of Cremophor EL in patients is limited. A previous paper using a bio-assay reported Cremophor EL levels up to 0.2% (Webster et al, 1993;Rischin et al, 1996). However, our preliminary information using the HPLC assay has revealed that the Cremophor EL levels are much higher (Sparreboom et al, 1996b;Van Tellingen et al, 1996). To address the issue if Cremophor EL can also be held responsible for the non-linear pharmacokinetics in patients, we have established the pharmacokinetic behaviour of this excipient in patients receiving 135 or 175 mg m -2 of paclitaxel (Taxol) by 3-or 24-h infusions. Because we have previously suggested that alterations in the affinity of paclitaxel toward plasma components might provide an explanation for the nonlinear plasma pharmacokinetics (Sparreboom et al, 1996b), we have now used an in vitro equilibrium dialysis assay and determination of paclitaxel in plasma ultrafiltrate to assess the influence of Cremophor EL on plasma binding of paclitaxel. PATIENTS AND METHODS PatientsThe patients included in this study received paclitaxel formulated in Cremophor EL:Ethanol 1...

Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview

“…In addition, Cremophor EL, which is responsible for the nonlinear pharmacokinetics of i.v. paclitaxel and for the severe hypersensitivity reactions, was not absorbed following oral administration of paclitaxel, as plasma levels of Cremophor EL were not detected [116][117][118]. This may be an additional advantage of oral paclitaxel administration [113,114].…”

Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer

“…14 This has been attributed to saturable transport 15 and saturable binding 16 but also to paclitaxel being trapped in micelles formed by adjuvant Cremophor EL (CrEL). [17][18][19] Considering the unbound clearance of paclitaxel instead of total plasma clearance can therefore be expected to give a clearer estimate of the effect of genetic variants on the elimination processes.…”

Ins and outs of taxanes

“…One factor is thought to be the sequestration of paclitaxel in the polar Cremophor EL micelles that circulate in blood, a phenomenon that may also account for the nonlinear pharmacokinetics of paclitaxel. 16 By contrast with the involvement of ATP-dependent efflux pumps in the cellular pharmacology of taxanes, an area that has continued to evolve, 17,18 the mechanism by which taxanes enter the cell has received relatively little attention as it has been presumed that these hydrophobic agents cross the plasma membrane by diffusion. However, taxane influx is not highly efficient, in that in cell culture experiments accumulation is measured in minutes, not seconds.…”