Individualized pharmacotherapy with paclitaxel.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Mielke
Stephan
S
Department of Hematology and Oncology, University Medical Center, Freiburg, Germany. mielkes@nhlbi.nih.gov
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000367:Age Factors; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D001663:Bilirubin / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D027361:Organic Anion Transporters / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use*; D010597:Pharmacogenetics / Q000379:methods*; D010599:Pharmacokinetics; D020641:Polymorphism, Single Nucleotide
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D027361:Organic Anion Transporters; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017239:Paclitaxel; D001663:Bilirubin