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The pharmacological advantage of prolonged dose rate gemcitabine is restricted to patients with variant alleles of cytidine deaminase c.79A>C.

Author(s): Metharom E, Galettis P, Manners S, Jelinek M, Liauw W, de Souza PL, Hoskins JM, Links M

Affiliation(s): Cancer Pharmacology Therapeutics Group Medical Oncology, St George and Sutherland Hospitals, Sydney, Australia.

Publication date & source: 2011-03, Asia Pac J Clin Oncol., 7(1):65-74. Epub 2010 Dec 30.

Publication type: Randomized Controlled Trial

AIM: Controversy exists over the optimal dosing for the nucleoside analogue gemcitabine. A pharmacological advantage is achieved by prolonging infusion times but evidence for a clinical benefit has been conflicting. We hypothesized that polymorphisms in genes involved in gemcitabine accumulation, particularly the cytidine deaminase CDA c.79A>C, may influence the optimal dosing regimen in individual patients. METHODS: DNA was collected from 32 patients participating in a randomized crossover study comparing 30-min with 100-min infusions of gemcitabine. The relationships between seven polymorphisms among three genes (CDA, RRM1 and DCK) and (i) gemcitabine triphosphate accumulation; (ii) gemcitabine-induced toxicity; and (iii) dose delivery were examined for each infusion time and week of administration. RESULTS: There were trends for increased accumulation of gemcitabine-triphosphate (GEM-TP) with the variant alleles of CDA c.79A>C, and RRM1-37C>A and -524T>C but none of these reached statistical significance in a univariate analysis. In a multivariable model there were significant effects of infusion duration and week of administration on GEM-TP accumulation. There were significant interactions between CDA c.79A>C (P=0.01) and RRM1-37C>A (P=0.019) genotypes, infusion time, and arm. More patients with one or two CDA c.79 variant alleles had doses delays (57 vs 13 %, P=0.03) and a pharmacological advantage for prolonged infusion after week 1. CONCLUSION: It is important to consider both pharmacokinetics and pharmacogenetics in optimizing gemcitabine accumulation. This represents a classical interaction between genes and environment and provides support for the consideration of both CDA genotype and infusion duration in development of an individualized dosing strategy. (c) 2010 Blackwell Publishing Asia Pty Ltd.

Page last updated: 2011-12-09

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