ABSTRACT
Anastrozole is a widely prescribed aromatase inhibitor for the therapy of estrogen receptor positive (ER+) breast cancer. We performed a genome-wide association study (GWAS) for plasma anastrozole concentrations in 687 postmenopausal women with ER+ breast cancer. The top single-nucleotide polymorphism (SNP) signal mapped across SLC38A7 (rs11648166, P = 2.3E-08), which we showed to encode an anastrozole influx transporter. The second most significant signal (rs28845026, P = 5.4E-08) mapped near ALPPL2 and displayed epistasis with the SLC38A7 signal. Both of these SNPs were cis expression quantitative trait loci (eQTL)s for these genes, and patients homozygous for variant genotypes for both SNPs had the highest drug concentrations, the highest SLC38A7 expression, and the lowest ALPPL2 expression. In summary, our GWAS identified a novel gene encoding an anastrozole transporter, SLC38A7, as well as epistatic interaction between SNPs in that gene and SNPs near ALPPL2 that influenced both the expression of the transporter and anastrozole plasma concentrations.
Subject(s)
Alkaline Phosphatase/genetics , Anastrozole/pharmacokinetics , Aromatase Inhibitors/pharmacokinetics , Epistasis, Genetic/genetics , Anastrozole/blood , Anastrozole/therapeutic use , Aromatase Inhibitors/blood , Aromatase Inhibitors/therapeutic use , Breast Neoplasms/drug therapy , Chromosomes, Human, Pair 16/genetics , Chromosomes, Human, Pair 2/genetics , Female , GPI-Linked Proteins/genetics , Genome-Wide Association Study , Genotype , Humans , Polymorphism, Single Nucleotide , Postmenopause , Receptors, Estrogen/biosynthesisABSTRACT
Oral anti-hormonal drugs are essential in the treatment of breast and prostate cancer. It is well known that the interpatient variability in pharmacokinetic exposure is high for these agents and exposure-response relationships exist for many oral anti-hormonal drugs. Yet, they are still administered at fixed doses. This could lead to underdosing and thus suboptimal efficacy in some patients, while other patients could be overdosed resulting in unnecessary side effects. Therapeutic drug monitoring (TDM), individualized dosing based on measured blood concentrations of the drug, could therefore be a valid option to further optimize treatment. In this review, we provide an overview of relevant clinical pharmacokinetic and pharmacodynamic characteristics of oral anti-hormonal drugs in oncology and translate these into practical guidelines for TDM. For some agents, TDM targets are not well established yet and as a reference the median pharmacokinetic exposure could be targeted (exemestane: minimum plasma concentration (Cmin) 4.1 ng/mL and enzalutamide: Cmin 11.4 mg/L). However, for most drugs, exposure-efficacy analyses could be translated into specific targets (abiraterone: Cmin 8.4 ng/mL, anastrozole: Cmin 34.2 ng/mL, and letrozole: Cmin 85.6 ng/mL). Moreover, prospective clinical trials have shown TDM to be feasible for tamoxifen, for which the exposure-efficacy threshold of its active metabolite endoxifen is 5.97 ng/mL. Based on the available data, we therefore conclude that individualized dosing based on drug concentrations is feasible and promising for oral anti-hormonal drugs and should be developed further and implemented into clinical practice.
Subject(s)
Antineoplastic Agents, Hormonal/pharmacokinetics , Breast Neoplasms/drug therapy , Drug Monitoring/methods , Prostatic Neoplasms/drug therapy , Administration, Oral , Anastrozole/blood , Androstenes/blood , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/blood , Aromatase Inhibitors/blood , Clinical Trials as Topic , Estrogen Receptor Modulators/blood , Estrogen Receptor Modulators/metabolism , Female , Humans , Letrozole/blood , Male , Prospective Studies , Tamoxifen/bloodABSTRACT
CONTEXT: Psoralen and anastrozole are always used together for breast cancer patients in Chinese clinics. OBJECTIVE: This study investigates the effects of psoralen on the pharmacokinetics of anastrozole in rats and its potential mechanism. MATERIALS AND METHODS: The pharmacokinetics of orally administered anastrozole (0.5 mg/kg) with (test group) or without (Control group) psoralen pretreatment (20 mg/kg/day for 10 days) in male Sprague-Dawley rats (six rats in each group) were investigated. The plasma concentration of anastrozole was determined using a sensitive and reliable LC-MS/MS method. Additionally, the effects of psoralen on the intestine transport and metabolic stability of anastrozole (1 µM) were investigated using a Caco-2 cell transwell model and rat liver microsome incubation systems. RESULTS: The results indicated that psoralen could significantly increase the Cmax (from 56.74 ± 3.17 ng/mL to 83.26 ± 6.87 ng/mL), and t1/2 (from 10.80 ± 1.05 to 14.29 ± 1.38 h) of anastrozole (p < 0.05). Psoralen could also significantly decrease the efflux ratio of anastrozole from 1.88 to 1.32 (p < 0.05). Additionally, the intrinsic clearance rates of anastrozole decreased significantly (from 62.83 to 43.97 µL/min/mg protein) (p < 0.05) with psoralen pretreatment in rat liver microsome incubation systems. DISCUSSION AND CONCLUSIONS: This study indicates that when the rats were pretreated with psoralen, the system exposure of anastrozole would be increased significantly. The results showed that the herb-drug interaction between psoralen and anastrozole might occur when they were co-administered, and future studies in humans also need to investigate its herb-drug interaction potential.
