Pharmacogenetic Screening of CYP3A and ABCB1 in Relation to Population Pharmacokinetics of Docetaxel

Abstract

Purpose: Despite the extensive clinical experience with docetaxel, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with the use of this anticancer drug. Large interindividual pharmacokinetic variability has been associated with variation in toxicity profiles. Genetic polymorphisms in drug-metabolizing enzymes and drug transporters could possibly explain the observed pharmacokinetic variability. The aim of this study was therefore to investigate the influence of polymorphisms in the CYP3A and ABCB1 genes on the population pharmacokinetics of docetaxel. Experimental Design: Whole blood samples were obtained from patients with solid tumors and treated with docetaxel to quantify the exposure to docetaxel. DNA was collected to determine polymorphisms in the CYP3A and ABCB1 genes with DNA sequencing. A population pharmacokinetic analysis of docetaxel was done using nonlinear mixed-effect modeling. Results: In total, 92 patients were assessable for pharmacokinetic analysis of docetaxel. A threecompartmental model adequately described the pharmacokinetics of docetaxel. Several polymorphisms in the CYP3A and ABCB1 genes were found, with allele frequencies of 0.54% to 48.4%. The homozygous C1236T polymorphism in the ABCB1 gene (ABCB1*8) was significantly correlated with a decreased docetaxel clearance (À25%; P = 0.0039). No other relationships between polymorphisms and pharmacokinetic variables reached statistical significance. Furthermore, no relationship between haplotypes of CYP3A and ABCB1and the pharmacokinetics could be identified. Conclusions: The polymorphism C1236T in the ABCB1 gene was significantly related to docetaxel clearance. Our current finding may provide a meaningful tool to explain interindividual differences in docetaxel treatment in daily practice.The anticancer drug docetaxel (Taxotere) is approved for the treatment of patients with early-stage, locally advanced and/or metastatic breast cancer, non -small-cell lung cancer, and androgen-independent metastatic prostate cancer. The recommended dose ranges from 75 to 100 mg/m 2 given as a 1-hour infusion once every 3 weeks. An important limitation associated with docetaxel use is the unpredictable interindividual variability in efficacy and toxicity. Potential causes for such variability in drug effects include the pathogenesis and severity of the disease being treated, the occurrence of unintended drug interactions, and impairment of hepatic and renal function (1). Despite the potential importance of these clinical variables in determining drug effects, it is recognized that inherited differences in metabolism and excretion can have an even greater effect on the efficacy and toxicity of drugs (1).The metabolism of docetaxel consists of a CYP3A-mediated oxidation of the tert-butylpropionate side chain, which results in the formation of four metabolites with reduced cytotoxic activity (2). The elimination pathway is mediated by the membrane-localized, energy-dependent drug efflux ABC tran...

Genotype and allele frequencies of MDR1 gene C1236T polymorphism in a Turkish population

“…It has been shown that the frequency of the mutant T allele was higher in late responders to oral prednisone than early responders for position 1236 in children with steroid-responsive nephrotic syndrome (Wasilewska et al, 2007). In the study of Bosch et al (2006), the homozygous C1236T polymorphism in the MDR1 gene was correlated with a decreased docetaxel clearance. In addition, Aarnoudse et al (2006) found that women with the TT genotype for position 1236 had a higher risk for the neuropsychiatric adverse effects of mefloquine.…”

PXR, CAR and HNF4α genotypes and their association with pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in Asian patients

“…8 With a larger data set of patients with uniformly favorable performance status and without the confounding factor of previous chemotherapy treatment, we again could not find a correlation between CYP3A5*3 and docetaxel disposition or neutrophil toxicity, confirming our previous finding and that of other investigators on the impact of this SNP. 8,32 This study is a genotype-phenotype study of the transcriptional regulators of CYP3A4, CYP3A5 and ABCB1 with respect to cytotoxic chemotherapy. PXR, CAR and HNF4a were found to be well conserved in our population, and could not explain the inter-individual variability of docetaxel.…”

A Comparison of the Pharmacokinetics and Pharmacodynamics of Docetaxel between African-American and Caucasian Cancer Patients: CALGB 9871

“…Our ABCB1 genotyping did not reveal any genotype-related differences in docetaxel clearance or hematologic pharmacodynamics between ethnic groups or any ABCB1 genotype relationships with docetaxel clearance or hematologic pharmacodynamics in the pooled patient population (data not shown). Interestingly, Bosch et al (44) studied 92 cancer patients who received docetaxel and found that patients who were homozygous (n = 19) for the ABCB1*8 (C1236T) polymorphism had a 25% reduction in docetaxel clearance compared with wild-type patients (n = 30). In contrast, Tran et al (45) suggested that patients with the ABCB1 T3435T genotype (n = 10) compared with patients with the C3435C genotype (n = 11) had an increased incidence of grade 3 neutropenia (100% versus 54.5%; P = 0.046).…”