Academic Medical Center, University of Amsterdam, Emma Childrens Hospital and Department of Clinical Chemistry, Amsterdam, the
Clin Pharmacokinet. 2012 Mar 1;51(3):163-74. doi: 10.1007/BF03257473.
Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-fluorouracil (5FU) and DPD deficiency is an important pharmacogenetic syndrome. So far, only very limited information is available regarding the pharmacokinetics of 5FU in patients with a (partial) DPD deficiency and no limited sampling models have been developed taking into account the non-linear pharmacokinetic behaviour of 5FU. The aim of this study was to evaluate the pharmacokinetics of 5FU and to develop a limited sampling strategy to detect decreased 5FU elimination in patients with a c.1905+1G>A-related DPD deficiency.
Thirty patients, heterozygous for the c.1905+1G>A mutation in DPYD, and 18 control patients received a dose of 5FU 300 mg/m2 and/or 5FU 450 mg/m2, followed by pharmacokinetic analysis of the 5FU plasma levels. A population pharmacokinetic analysis was performed in order to develop a compartmental pharmacokinetic model suitable for a limited sampling strategy. Clinical aspects of treating DPD-deficient patients with 5FU-based chemotherapy were assessed from the retrospectively collected clinical data.
In a two-compartment model with Michaelis-Menten elimination, the mean maximum enzymatic conversion capacity (V(max)) value was 40% lower in DPD-deficient patients compared with controls (p < 0.001). Using a limited sampling strategy, with V(max) values calculated from 5FU concentrations at 30 or 60 minutes, significant differences were observed between DPD-deficient patients and controls at both dose levels (p < 0.001). The positive predictive value and negative predictive value for V(max), calculated from 5FU levels at 60 minutes, were 96% and 88%, respectively, in patients treated with a single dose of 5FU 300 mg/m2. All seven DPD-deficient patients (two males and five females) who had been genotyped prior to initiation of standard 5FU-containing chemotherapy developed grade 3-4 toxicity, with one case of lethal toxicity in a female patient. No grade 4 toxicity or lethal outcome was observed in 13 DPD-deficient patients treated with reduced doses of 5FU. The average dose of 5FU in DPD-deficient patients with mild toxicity (grade ≤2) was 61 ± 16% of the normal 5FU dose (n = 10).
Profound differences in the elimination of 5FU could be detected between DPD-deficient patients and control patients. Pharmacokinetic 5FU profiling, using a single 5FU concentration at 60 minutes, may be useful for identification of DPD-deficient patients in order to reduce severe toxicity. Furthermore, treatment of DPD-deficient patients with standard 5FU-containing chemotherapy was associated with severe (lethal) toxicity.
二氢嘧啶脱氢酶（DPD）是 5-氟尿嘧啶（5FU）代谢的初始酶，DPD 缺乏是一种重要的药物遗传学综合征。到目前为止，关于 DPD 部分缺乏患者 5FU 的药代动力学的信息非常有限，并且尚未开发出考虑到 5FU 的非线性药代动力学行为的有限采样模型。本研究旨在评估 5FU 的药代动力学，并开发一种有限采样策略来检测 DPD 部分缺乏患者 5FU 消除减少。
30 名杂合 c.1905+1G>A 突变的 DPYD 患者和 18 名对照患者接受 5FU 300mg/m2 和/或 5FU 450mg/m2 剂量，然后对 5FU 血浆水平进行药代动力学分析。为了开发适合有限采样策略的房室药代动力学模型，进行了群体药代动力学分析。从回顾性收集的临床数据中评估了基于 5FU 的化疗治疗 DPD 缺乏患者的临床方面。
在具有米氏消除的两室模型中，与对照组相比，DPD 缺乏患者的平均最大酶转化能力（V(max)）值低 40%（p<0.001）。使用有限采样策略，使用 30 或 60 分钟时的 5FU 浓度计算 V(max)值，在两个剂量水平下，DPD 缺乏患者与对照组之间均观察到显著差异（p<0.001）。在接受 5FU 300mg/m2 单剂量治疗的患者中，从 60 分钟时的 5FU 水平计算的 V(max)的阳性预测值和阴性预测值分别为 96%和 88%。在开始标准 5FU 化疗之前进行基因分型的 7 名 DPD 缺乏患者（2 名男性和 5 名女性）均发生了 3-4 级毒性，1 名女性患者发生了致命毒性。在接受减少剂量的 5FU 治疗的 13 名 DPD 缺乏患者中未观察到 4 级毒性或致死结果。轻度毒性（等级≤2）的 DPD 缺乏患者 5FU 的平均剂量为正常 5FU 剂量的 61±16%（n=10）。
DPD 缺乏患者和对照组患者之间可以检测到 5FU 消除的明显差异。使用 60 分钟时的单个 5FU 浓度进行 5FU 药代动力学分析，可能有助于识别 DPD 缺乏患者，以降低严重毒性。此外，DPD 缺乏患者接受标准的含 5FU 化疗与严重（致命）毒性相关。
