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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden; 2 Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; 3 Department of Medical Oncology, Erasmus MC - Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; 4 Tumor Biology Center at the Albert-Ludwigs University, 5 Department of Hematology and Oncology, University of Freiburg Medical Center, Freiburg im Breisgau, Germany; 6 Division of Medical Oncology, Istituto Nazionale Tumori, Milan, Italy; and 7 Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, Maryland
Requests for reprints: Alex Sparreboom, Clinical Pharmacology Research Core, Medical Oncology Branch, National Cancer Institute, 9000 Rockville Pike, Building 10, Room 5A01, Bethesda, MD 20892. Phone: 301-402-9498; Fax: 301-402-8606; E-mail: SparrebA{at}mail.nih.gov.
Purpose: To retrospectively evaluate the effects of six known allelic variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes on the pharmacokinetics of the anticancer agent paclitaxel (Taxol).
Experimental Design: A cohort of 97 Caucasian patients with cancer (median age, 57 years) received paclitaxel as an i.v. infusion (dose range, 80-225 mg/m2). Genomic DNA was analyzed using PCR RFLP or using Pyrosequencing. Pharmacokinetic variables for unbound paclitaxel were estimated using nonlinear mixed effect modeling. The effects of genotypes on typical value of clearance were evaluated with the likelihood ratio test within NONMEM. In addition, relations between genotype and individual pharmacokinetic variable estimates were evaluated with one-way ANOVA.
Results: The allele frequencies for the CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP3A4*3, CYP3A5*3C, and ABCB1 3435C>T variants were 0.7%, 9.2%, 2.1%, 0.5%, 93.2%, and 47.1%, respectively, and all were in Hardy-Weinberg equilibrium. The population typical value of clearance of unbound paclitaxel was 301 L/h (individual clearance range, 83.7-1055 L/h). The CYP2C8 or CYP3A4/5 genotypes were not statistically significantly associated with unbound clearance of paclitaxel. Likewise, no statistically significant association was observed between the ABCB1 3435C>T variant and any of the studied pharmacokinetic variables.
Conclusions: This study indicates that the presently evaluated variant alleles in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not explain the substantial interindividual variability in paclitaxel pharmacokinetics.
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