Pharmacogenetics-Guided Phase I Study of Capecitabine on an Intermittent Schedule in Patients with Advanced or Metastatic Solid Tumours
| Autor: | Xn-Yii Lim, Wei Peng Yong, Sing-Huang Tan, Siew-Eng Lim, Ying-Kiat Zee, Soo-Chin Lee, Andrea Li Ann Wong, Nicholas Syn, Richie Soong, Marie Loh, Boon Cher Goh, Benjamin Chuah, Danny Chan, R.A. Soo, Lingzhi Wang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine Oncology medicine.medical_specialty Genotype Maximum Tolerated Dose Antineoplastic Agents Breast Neoplasms Thymidylate synthase Article Capecitabine 03 medical and health sciences 0302 clinical medicine Clinical Protocols Pharmacokinetics Internal medicine medicine Humans Drug Dosage Calculations Dosing Neoplasm Metastasis Adverse effect Aged Neoplasm Staging Polymorphism Genetic Multidisciplinary biology business.industry Cancer Thymidylate Synthase Middle Aged medicine.disease Pharmacogenomic Testing Surgery Enhancer Elements Genetic 030104 developmental biology 030220 oncology & carcinogenesis Toxicity biology.protein Female Colorectal Neoplasms business Pharmacogenetics medicine.drug |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep27826 |
| Popis: | The FDA-approved starting dosage of capecitabine is 1,250 mg/m2, and market research indicates that U.S. physicians routinely prescribe 1,000 mg/m2. Retrospective analyses however report reduced toxicity and efficacy in a subset of patients with the 3R/3R genotype of the thymidylate synthase gene enhancer region (TSER). This study sought to develop TSER genotype-specific guidelines for capecitabine dosing. Capecitabine was dose-escalated in advanced and/or metastatic cancer patients with TSER 3R/3R (Group A; N = 18) or 2R/2R + 2R/3R (Group B; N = 5) from 1,250 to 1,625 mg/m2 b.i.d., every 2 weeks on/1 week off for up to 8 cycles. Parent and metabolites pharmacokinetics, adverse events, and tumour response were assessed. The maximum tolerated and recommended doses in 3R/3R patients are 1,625 mg/m2 and 1,500 mg/m2. At 1,500 mg/m2, one in nine 3R/3R patients experienced a dose-limiting toxicity. Dosing guidelines for 2R/2R + 2R/3R remain undetermined due to poor accrual. The results indicate that 3R/3R patients may be amenable to 1,500 mg/m2 b.i.d. on an intermittent schedule, and is the first to prospectively validate the utility of TSER pharmacogenetic-testing before capecitabine treatment. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|