Bernier J, Stratford M R, Denekamp J, Dennis M F, Bieri S, Hagen F, Kocagöncü O, Bolla M, Rojas A
Cantonal Department of Radiation Oncology, San Giovanni Hospital, Bellinzona, Switzerland.
Radiother Oncol. 1998 Aug;48(2):123-33. doi: 10.1016/s0167-8140(98)00048-6.
The EORTC has initiated studies to combine nicotinamide with carbogen in accelerated fractionation schedules (ARCON), since for some tumour types, acute and chronic hypoxia as well as treatment protraction may prejudice the outcome of radiotherapy. The tolerable dose of nicotinamide and the optimal interval for administration need to be ascertained.
Full pharmacokinetic profiles of nicotinamide concentrations in plasma were analyzed repeatedly in 15 patients to determine the inter- and intra-patient variability in peak plasma concentrations and the optimum times for administering nicotinamide as a radiosensitizer.
Nicotinamide (Nicobion) was administered in tablet form to patients with advanced head and neck and non-small cell lung carcinomas. A standard 6 g dose was given regardless of body weight after an overnight fast and at least 30 min before breakfast. In 15 patients, blood samples were taken prior to and 1, 2, 4, 6, 8, 12 and 24 h after administration of the drug. This full profile was determined on two to four occasions for the head and neck cancer patients and on two occasions for the lung cancer patients. For each profile, the maximum concentration of nicotinamide (Cmax), time to peak plasma concentration (Tmax), elimination half-lives (t1/2) and area under the curve (AUC) were determined. Compliance was recorded and nausea and vomiting were graded on a 0-3 scale. Complete profiles of the five major metabolites were also obtained.
In the 48 complete sets of blood samples, peak plasma concentrations ranged from 787 to 2312 nmol/ml with a median value of 1166 nmol/ml. The peak plasma concentration was achieved at 1 h in only 54% of the pharmacokinetic profiles, but at this time 92% of the profiles had already exceeded the target concentration of 700 nmol/ml, the level required in the mouse for tumour radiosensitization. The median t1/2 for all 15 cases was 9.3 h, with minimum and maximum values of 4.2 and 26.8 h. The highest concentrations of nicotinamide metabolites were found to be the N-oxide, 2-pyridone and 1-methylnicotinamide. The toxicity (nausea and vomiting) was scored and found not to be correlated with any of the pharmacokinetic parameters.
The plasma concentrations considered necessary to radiosensitize can easily be exceeded with a dose of 6 g taken as 12 x 500 mg in tablet form; 700 nmol/ml was achieved in all patients and apparently would have been achieved in most even with a considerable reduction in dose. An adequate time between administration and radiotherapy appeared to be 1 h with this drug formulation for 92% of the profiles.
欧洲癌症研究与治疗组织（EORTC）已开展研究，将烟酰胺与碳合氧混合用于加速分割放疗方案（ARCON），因为对于某些肿瘤类型，急性和慢性缺氧以及治疗延长可能会影响放疗效果。需要确定烟酰胺的可耐受剂量和最佳给药间隔。
对15例患者反复分析血浆中烟酰胺浓度的完整药代动力学特征，以确定患者间和患者内血浆峰值浓度的变异性以及将烟酰胺作为放射增敏剂给药的最佳时间。
以片剂形式向晚期头颈癌和非小细胞肺癌患者给药烟酰胺（烟酰胺片）。无论体重如何，在禁食过夜后且早餐前至少30分钟给予标准剂量6克。对15例患者，在给药前以及给药后1、2、4、6、8、12和24小时采集血样。对头颈癌患者进行两到四次这种完整的检测，对肺癌患者进行两次检测。对于每次检测，确定烟酰胺的最大浓度（Cmax）、血浆浓度达峰时间（Tmax）、消除半衰期（t1/2）和曲线下面积（AUC）。记录依从性，并将恶心和呕吐按0 - 3级评分。还获得了五种主要代谢物的完整图谱。
在48套完整的血样中，血浆峰值浓度范围为787至2312纳摩尔/毫升，中位数为1166纳摩尔/毫升。在仅54%的药代动力学图谱中，血浆峰值浓度在1小时时达到，但此时92%的图谱已超过700纳摩尔/毫升的目标浓度，即小鼠肿瘤放射增敏所需的水平。15例患者的中位数t1/2为9.3小时，最小值和最大值分别为4.2小时和26.8小时。发现烟酰胺代谢物的最高浓度为N - 氧化物、2 - 吡啶酮和1 - 甲基烟酰胺。对毒性（恶心和呕吐）进行评分，发现其与任何药代动力学参数均无相关性。
以12片500毫克的片剂形式服用6克剂量，很容易超过放射增敏所需的血浆浓度；所有患者均达到了700纳摩尔/毫升，而且显然即使剂量大幅降低，大多数患者也能达到该浓度。对于92%的图谱，使用这种药物制剂时，给药与放疗之间的适当时间似乎为1小时。
