Pharmacokinetic modeling of paclitaxel encapsulation in Cremophor EL micelles

Nonlinear disposition of paclitaxel (Taxol) in cancer patients has been des cribed in several studies, but the underlying mechanism is still st matter of speculation. Previously, we have shown in vitro that the paclitaxel form ulation vehicle, Cremophor EL (CrEL): alters the blood distribution of pacl itaxel as a result of entrapment of the compound in circulating CrEL micell es, thereby reducing the free drug fraction available for cellular partitio ning. 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. Se ven 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/m(2) (Cr EL dose level, 18.8, 14.6, and 11.3 ml/m(2), respectively). Patient samples were collected up to 24 h after the start of infusion, and analyzed by hig h-performance liquid chromatography. Paclitaxel peak levels and areas under the curve in whole blood increased linearly with dose, whereas plasma leve ls showed substantial deviation from linearity. This was shown to be caused by a CrEL concentration-dependent decrease in paclitaxel uptake in blood c ells, as reflected by the blood:plasma concentration ratios which altered s ignificantly from 0.83 +/- 0. 11 (at 135 mg/m(2)) to 0.68 +/- 0.07 (at 225 mg/m(2)). It is concluded that the nonIinear disposition of paclitaxel is r elated to paclitaxel dose-related levels of the formulation vehicle CrEL, l eading to a disproportionate drug accumulation in the plasma fraction. The pharmacokinetic model developed accurately described the data, and will hel p guide future development and refinement of clinical protocols, especially in defining the exposure measure best linked to paclitaxel effects and tox icities.