The anticancer drug docetaxel (Taxotere) is formulated in the nonionic surfactant polysorbate 80 (Tween 80). Early in the clinical development of docetaxel, it became clear that docetaxel administration is associated with the occurrence of unpredictable (acute) hypersensitivity reactions and cumulative fluid retention. These side-effects have been attributed, in part, to the presence of polysorbate 80 and have consequently initiated research focused on the development of a less-toxic, better-tolerated polysorbate 80-free formulation of docetaxel. More recently, there is an increasing interest in developing a (polysorbate 80-free) docetaxel formulation that selectively targets malignant tissue, thereby increasing efficacy while decreasing the occurrence of side-effects related to wide and nonspecific body distribution. This review aims to discuss the preclinical and clinical results of pharmaceutical strategies [PEGylated (immuno)liposomal docetaxel, docetaxel-fibrinogen-coated olive oil droplets, docetaxel encapsulated nanoparticle-aptamer bioconjugates, submicronic dispersion formulation] to develop an alternative, solvent-free, delivery form for docetaxel characterized by increased efficacy and decreased toxicity.

PURPOSE Paclitaxel is used for the treatment of several solid tumors and displays a high inter-individual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side-effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity. EXPERIMENTAL DESIGN In an exploratory cohort of patients (n=261) treated with paclitaxel, neurotoxicity incidence and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by HPLC or LC-MS/MS, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by non-linear mixed effects modeling (NONMEM). Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n=239). RESULTS Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P <0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T>0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (odds ratio = 19.1; P = 0.001). CONCLUSIONS Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment.

Purpose: Docetaxel pharmacokinetic (PK) parameters, notably clearance and exposure (AUC), are characterized by large interindividual variability. The purpose of this study was to evaluate the effect of PKguided [area under the plasma concentration versus time curve (AUC) targeted], individualized docetaxel dosing on interindividual variability in exposure.Experimental Design: A limited sampling strategy in combination with a validated population PK model, Bayesian analysis, and a predefined target AUC was used. Fifteen patients were treated for at least 2 courses with body surface area-based docetaxel and 15 with at least 1 course of PK-guided docetaxel dosing.Results: Interindividual variability (SD of ln AUC) was decreased by 35% (N ¼ 15) after 1 PK-guided course; when all courses were evaluated, variability was decreased by 39% (P ¼ 0.055). PK-guided dosing also decreased the interindividual variability of percentage decrease in white blood cell and absolute neutrophil counts by approximately 50%.Conclusions: Further research is required to determine whether the decrease in PK variability can contribute to a reduction in interindividual variability in efficacy and toxicity. Clin Cancer Res; 17(2); 353-62.Ó2011 AACR.