Pharmacokinetic modeling of paclitaxel encapsulation in Cremophor EL micelles

Abstract

Nonlinear disposition of paclitaxel (Taxol) in cancer patients has been described in several studies, but the underlying mechanism is still a matter of speculation. Previously, we have shown in vitro that the paclitaxel formulation vehicle, Cremophor EL (CrEL), alters the blood distribution of paclitaxel as a result of entrapment of the compound in circulating CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. Based on these findings, we prospectively re-evaluated the linearity of paclitaxel disposition in patients using whole blood and plasma analysis, and sought to define a new pharmacokinetic model to describe the data. Seven patients with solid tumors were treated with paclitaxel infused over 3 h, each at consecutive 3-weekly dose levels of 225, 175 and 135 mg/m2 (CrEL dose level, 18.8, 14.6, and 11.3 ml/m2, respectively). Patient samples were collected up to 24 h after the start of infusion, and analyzed by high-performance liquid chromatography. Paclitaxel peak levels and areas under the curve in whole blood increased linearly with dose, whereas plasma levels showed substantial deviation from linearity. This was shown to be caused by a CrEL concentration-dependent decrease in paclitaxel uptake in blood cells, as reflected by the blood:plasma concentration ratios which altered significantly from 0.83 +/- 0.11 (at 135 mg/m2) to 0.68 +/- 0.07 (at 225 mg/m2). It is concluded that the nonlinear disposition of paclitaxel is related to paclitaxel dose-related levels of the formulation vehicle CrEL, leading to a disproportionate drug accumulation in the plasma fraction. The pharmacokinetic model developed accurately described the data, and will help guide future development and refinement of clinical protocols, especially in defining the exposure measure best linked to paclitaxel effects and toxicities.

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

“…The expected phenomenon of apparent decrease in clearance with increasing dose of paclitaxel was observed, which may cloud the interpretation of any apparent interaction. This apparent nonlinearity in pharmacokinetics is now known to be due to the action of the solubilising agent Cremophor, which sequesters paclitaxel in a dose-dependent manner (van Zuylen et al, 2001). In conclusion, in the absence of a within patient crossover study, there appears to be no pharmacokinetic interaction between temozolomide and paclitaxel when given in combination.…”

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.…”

Phase I and Pharmacokinetic Study of Genexol-PM, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced Malignancies

“…However, the addition of CrEL has been shown to cause hypersensitivity reaction (HSR) and neuropathy (1)(2)(3). In addition, CrEL significantly alters the pharmacokinetics of paclitaxel (2)(3)(4)(5). The pharmacokinetic behavior of paclitaxel has been proposed to be distinctly nonlinear because the drug is trapped in micelles, making it less available for tissue distribution, metabolism, and biliary excretion, whereas CrEL-free paclitaxel appears to be linear (6,7).…”

“…It has been proposed to induce a cell cycle block distinct from that seen with paclitaxel (9) or to reverse the multidrug resistance phenotype (10,11). However, it is uncertain whether the plasma concentration of CrEL attainable during Taxol infusion is relevant in solid tumors (4,12,13). Collectively, the addition of CrEL is closely related with toxicity, inconvenience, less effective biodistribution, and special devices for the administration of paclitaxel.…”