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

Aim:
Controversy exists over the optimal dosing for the nucleoside analogue gemcitabine. A pharmaco-logical advantage is achieved by prolonging infusion times but evidence for a clinical benefit has beenconflicting. We hypothesized that polymorphisms in genes involved in gemcitabine accumulation, particu-larly the cytidine deaminaseCDAc.79A>C, may influence the optimal dosing regimen in individual patients.

Methods:
DNA was collected from 32 patients participating in a randomized crossover study comparing30-min with 100-min infusions of gemcitabine. The relationships between seven polymorphisms amongthree genes (CDA,RRM1andDCK) 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 thevariant alleles ofCDAc.79A>C, andRRM1-37C>A and -524T>C but none of these reached statisticalsignificance in a univariate analysis. In a multivariable model there were significant effects of infusionduration and week of administration on GEM-TP accumulation. There were significant interactions betweenCDAc.79A>C(P=0.01) and RRM1-37C>A(P=0.019) genotypes, infusion time, and arm. More patientswith one or twoCDAc.79 variant alleles had doses delays (57vs13 %,P=0.03) and a pharmacologicaladvantage for prolonged infusion after week 1.

Conclusion:
It is important to consider both pharmacokinetics and pharmacogenetics in optimizinggemcitabine accumulation. This represents a classical interaction between genes and environment andprovides support for the consideration of both CDA genotype and infusion duration in development of anindividualized dosing strategy