Individualized pharmacotherapy with paclitaxel

Abstract

More than two decades of clinical experience with paclitaxel as an anticancer drug have contributed significantly to the optimization of today's application schemes and patients' safety. Recent knowledge about interindividual pharmacokinetic variability and population modeling provides a novel scientific basis for an improved and individualized therapeutic approach. Age, gender and bilirubin levels were shown to be associated with an altered pharmacokinetic profile. Prolonged exposure to paclitaxel concentrations exceeding the thresholds of 0.05 or 0.1 micromol/l were predictive for neutropenia, peripheral neuropathy and survival. Due to substantial interindividual diversity observed in paclitaxel pharmacokinetics actual research focuses on common single nucleotide polymorphisms in genes encoding metabolizing enzymes and drug transporters such as CYP450, P-glycoprotein and the organic anion transporting polypeptide OATP1B3. Polymorphisms of ABCB1 encoding P-glycoprotein were found to be associated with neutropenia and neurotoxicity. A haplotype of CYP3A4 was associated with paclitaxel pharmacokinetics. Several demographic, pharmacokinetic and genetic covariables that have been identified to influence toxicity and tumor responses following chemotherapy with paclitaxel are discussed with regard to their transferability into a bedside approach.