SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours.

Gemcitabine is used for the treatment of several solid tumours and exhibits high inter-individual pharmacokinetic variability. In this study, we explore possible predictive covariates on drug and metabolite disposition. Forty patients were enrolled. Gemcitabine and dFdU concentrations in the plasma and dFdCTP concentrations in peripheral blood mononuclear cell were measured to 72 h post infusion, and pharmacokinetic parameters were estimated by nonlinear mixed-effects modelling. Patient-specific covariates were tested in model development. The pharmacokinetics of gemcitabine was best described by a two-compartment model with body surface area, age and NT5C2 genotype as significant covariates. The pharmacokinetics of dFdU and dFdCTP were adequately described by three-compartment models. Creatinine clearance and cytidine deaminase genotype were significant covariates for dFdU pharmacokinetics. Rate of infusion of <25 mg m−2 min−1 and the presence of homozygous major allele for SLC28A3 (CC genotype) were each associated with an almost two-fold increase in the formation clearance of dFdCTP. Prolonged dFdCTP systemic exposures (⩾72 h) were commonly observed. Infusion rate <25 mg m−2 min−1 and carriers for SLC28A3 variant were each associated with about two-fold higher dFdCTP formation clearance. The impacts of these covariates on treatment-related toxicity in more selected patient populations (that is, first-line treatment, single disease state and so on) are not yet clear.

吉西他滨用于治疗多种实体瘤，且个体间药代动力学差异较大。在本研究中，我们探讨了药物及代谢物处置的可能预测协变量。 招募了40名患者。测量了输注后72小时内血浆中吉西他滨和二氟脱氧尿苷（dFdU）的浓度以及外周血单核细胞中二氟脱氧胞苷三磷酸（dFdCTP）的浓度，并通过非线性混合效应模型估算药代动力学参数。在模型构建过程中对患者特异性协变量进行了检验。 吉西他滨的药代动力学用一个二室模型描述最佳，其中体表面积、年龄和NT5C2基因型为显著协变量。dFdU和dFdCTP的药代动力学用三室模型充分描述。肌酐清除率和胞苷脱氨酶基因型是dFdU药代动力学的显著协变量。输注速率<25mg·m⁻²·min⁻¹以及SLC28A3存在纯合显性等位基因（CC基因型）均与dFdCTP的生成清除率几乎翻倍相关。 经常观察到dFdCTP全身暴露时间延长（⩾72小时）。输注速率<25mg·m⁻²·min⁻¹以及SLC28A3变异体携带者均与dFdCTP生成清除率提高约两倍相关。这些协变量对更具选择性的患者群体（即一线治疗、单一疾病状态等）中与治疗相关的毒性的影响尚不清楚。