Effect of CYP3A4, CYP3A5, and ABCB1 Polymorphisms on Intravenous Tacrolimus Exposure and Adverse Events in Adult Allogeneic Stem Cell Transplant Patients.

Pharmacogenetics influences oral tacrolimus exposure; however, little data exist regarding i.v. tacrolimus. We investigated the impact of genetic polymorphisms in CYP3A4, CYP3A5, and ABCB1 on i.v. tacrolimus exposure and toxicity in adult patients receiving an allogeneic hematopoietic stem cell transplant for hematologic malignancies. Germline DNA was extracted from buccal swabs and genotyped for CYP3A4, CYP3A5, and ABCB1 polymorphisms. Continuous i.v. infusion of tacrolimus .03 mg/kg/day was initiated on day +5 post-transplant, and steady-state blood concentrations were measured 4days later. We evaluated the association between phenotypes and prevalence of nontherapeutic target concentrations (below or above 5 to 15 ng/mL) as well as tacrolimus-related toxicities. Of 63 patients, 28.6% achieved the target concentration; 71.4% were >15ng/mL, which was more common in CYP3A4 intermediate/normal metabolizers (compared with rapid) and those with at least 1 ABCB1 C2677T loss-of-function allele (P < .05). ABCB1 C2677T was significantly associated with concentrations >15ng/mL (odds ratio, 6.2; 95% confidence interval, 1.8 to 23.6; P = .004) and tacrolimus-related toxicities (odds ratio, 7.5; 95% confidence interval, 1.6 to 55.2; P = .02). ABCB1 C2677T and CYP3A4 are important determinants of i.v. tacrolimus exposure, whereas ABCB1 C2677T also impacts tacrolimus-related toxicities in stem cell transplants.

Personalizing aromatase inhibitor therapy in patients with breast cancer.

BACKGROUND: Aromatase inhibitors are the mainstay of therapy for patients with hormone receptor-positive breast cancer in both adjuvant and metastatic settings. Their use in clinical practice has been challenged by significant inter-individual variability in response and tolerability. Hence, the purpose of this paper is to provide a succinct review of the literature on the genetic factors contributing to this variability. DESIGN: A systematic search in PUBMED was conducted to identify studies that investigated the association between germline polymorphisms and disposition, clinical response and toxicities of aromatase inhibitors, as well as those evaluating the implications of mutations in ESR1 on clinical response. RESULTS: Polymorphisms in genes coding for phase I and phase II enzymes (pharmacokinetic genes) significantly modulated exposure to aromatase inhibitors; however, there is a paucity of data linking interindividual variability in drug exposure to clinical response. Furthermore, pharmacogenetic studies interrogating relationship between polymorphisms in CYP19A1 (the target site of aromatase inhibitors, i.e. a pharmacodynamic gene) and response yielded conflicting results. Acquired mutations in ESR1 receptors have been identified as the underlying mechanism of resistance to aromatase inhibitors, and likely predict drug response. Although some pharmacogenetic studies have implicated polymorphisms in CYP19A1 and ESR1 with drug-related side effects, the putative role of these genes in predicting toxicity warrants further validation. CONCLUSION: Genetic polymorphisms in pharmacokinetic and pharmacodynamic genes appear to influence aromatase inhibitor disposition, response and/or toxicity; however, prospective interventional studies are needed to understand the application of genomics to personalize aromatase inhibitor therapy in breast cancer patients.