Pharmacokinetic and pharmacogenetic profiling in solid cancer patients

Abstract

The potential for patient-based drug tailoring has recently been recognised with the objectives of improving treatment activity and limiting toxicity. There are various possibilities to address interpatient variability in anticancer drug activity and toxicity. First, interpatient variability in drug metabolism can result in variable drug exposure and - activity. Second, germline DNA polymorphisms in drug-metabolising genes potentially impact individual anticancer drug metabolism and clearance, while polymorphisms in drug-target genes might underly variability in drug activity independent of drug pharmacokinetics. Third, drug interactions are also important with respect to drug activity and side effects. Clinical studies on paclitaxel pharmacokinetics and pharmacodynamics The influence of anthropometric and biochemical covariates on the pharmacokinetics of paclitaxel was assessed in a retrospective study, pooling individual data from 168 patients with solid tumors receiving intravenous paclitaxel, mostly as a single agent (chapter 1.1.4). Patient gender was found to significantly affect paclitaxel elimination, in that male patients had a roughly 20% higher maximal elimination capacity as compared to female patients. A further study analysed the quantitative impact of hepatic impairment on paclitaxel pharmacology and toxicity (chapter 1.1.5). Paclitaxel elimination capacity was shown to decrease with deteriorating liver function. Additionally, liver impairment was a significant predictor of increased sensibility to paclitaxel-related, hematological toxicity. A third prospective clinical study included 139 patients with ovarian cancer after cytoreductive surgery, receiving additive paclitaxel and carboplatin (chapter 1.1.6). The time above paclitaxel threshold concentration of 0.05 mol/L was found to predict chemotherapy-related neutropenia as well as progression-free survival, while carboplatin exposure was found to predict chemotherapy-related thrombocytopenia. Pharmacokinetic and pharmacogenetic profiling in solid cancer patients receiving platinum-based combination chemotherapy In the first study, 25 gene polymorphisms within 10 drug pathway-associated genes (DPYD, TYMS, MRP2, GSTM1, GSTT1, GSTP1, ERCC1, ERCC2, XRCC1, MTHFR) were examined from peripheral blood in 64 patients with advanced colorectal cancer receiving oxaliplatin and the oral 5-fluorouracil prodrug capecitabine (chapter 2.1). Potential associations between gene polymorphisms, anticancer drug pharmacokinetics, clinical outcome and toxicity were examined. GSTP1-105Val and MTHFR-677Val were significantly associated with improved treatment response. Patients with two mutant GSTP1-105Val alleles had a longer progression-free survival as compared to wild-type or heterozygous GSTP1-Ile105Val patients (11.8 vs. 8.5 months), as had patients with two mutant MTHFR-677Val alleles compared to patients with wild-type or heterozygous MTHFR-Ala677Val (13.5 vs 8.5 months), and patients with at least one ERCC2-751Gln allele as compared to patients with wild-type ERCC2-Lys751Gln (12.3 vs 8.4 months). The TYMS high-expression genotype was significantly associated with a shorter progression-free survival as compared to patients with the low-expression genotype (7.2 vs. 10.5 months). Additionally, drug pathway-associated genes were predictors of anticancer drug-related toxicity, i.e. mutant GSTP1-105Val for worse cumulative polyneuropathy and mutant DPD A2846T (DPYD*9B) for severe diarrhea. In conclusion, these data suggest oxaliplatin/capecitabine pathway-associated genes to be useful predictors of drug activity and toxicity. In the second study, 44 polymorphisms within 16 drug pathway-associated genes (TYMS, MTHFR, GSTP1, -M1, -T1, DPYD, XRCC1, XRCC3, XPD, ERCC1, RECQ1, RAD54L, ABCB1, ABCC2, ABCG2, UGT2B7) were analysed in 76 patients with advanced gastroesophageal cancer receiving cisplatin, epirubicin and capecitabine. XPD 751Gln, XRCC3 241Met and DPYD 543Val were all significantly associated with improved treatment response. The TYMS high-expression genotype was significantly associated with a worse progression-free survival as compared to patients with the low-expression genotype. Patients homozygous mutant for DPYD 543Val had a superior progression-free survival as compared to patients with wild-type or heterozygous DPYD Ile543Val (10.9 vs. 6.8 months). Additionally, drug pathway-associated genes were predictors of anticancer drug-related toxicity, i.e. mutant DPYD Met166Val (*9A), DPYD Asp949Val (*9B) and DPYD IVS14+G>A for severe diarrhea, DPYD Met166Val (*9A), DPYD Asp949Val (*9B) for palmoplantar erythrodysesthesia, and mutant GSTP1-105Val for worse cumulative polyneuropathy. These data suggest cisplatin/epirubicin/capecitabine pathway-associated genes to be useful predictors of drug activity and toxicity