Hoskin P J, Stratford M R, Saunders M I, Hall D W, Dennis M F, Rojas A
CRC Tumour Biology and Radiation Therapy Group, Mount Vernon Hospital, Northwood, Middlesex, UK.
Int J Radiat Oncol Biol Phys. 1995 Jul 15;32(4):1111-9. doi: 10.1016/0360-3016(95)00022-q.
To determine nicotinamide pharmacokinetics in patients undergoing accelerated radiotherapy with the CHART regimen (continuous, hyperfractionated, accelerated radiotherapy) and given nicotinamide on a daily basis. The aim was to establish the pharmacokinetic profiles and their reproducibility during repeated administration, the maximum tolerated dose with fractionated radiotherapy, whether such a dose achieves sufficiently high plasma levels for radiosensitization, the optimal time interval between nicotinamide and irradiation, and toxic side effects.
Nicotinamide plasma concentrations were determined using high performance liquid chromatography in 11 patients with advanced carcinomas of the head and neck and rectum being treated with CHART (36 fractions in 12 days). Kinetic profiles on the first day of radiotherapy and residual 24-h values were obtained in 10 patients; in four of these, full profiles were repeated two or three times during the course of treatment. In one other, a single sample per day was taken four times over the 12-day period. Doses of 80, 90, or 100 mg/kg/day were given 90 min prior to the second radiotherapy fraction on each day.
A dose of 80 mg/kg/day was well tolerated by all the patients. However, an increase of 10-25% in dose led to significant drug accumulation and major clinical toxicity, and none of the patients in the dose-escalation arm completed the planned regimen. Large interpatient variations in absolute peak concentrations were seen from 0.4 to 1.4 mumol/ml (mean 0.9 +/- 0.3; standard deviation (SD)). Of the five samples with the lowest peak levels, four were obtained from one patient. The time taken to peak concentration was also very variable from 0.8 to 4 h (mean 2.1 +/- 1.3 h; SD). In 70% of the samples, absolute plasma levels > or = 0.7 mumol/ml were reached within 1-2 h after administration and maintained for up to 6 h (mean 2.8 +/- 1.8 h; SD). There was a small but nonsignificant increase in the half-life of nicotinamide when the dose was increased from 80 to 90 or 100 mg/kg (7.1 h and 8.6 h, respectively).
In an accelerated regimen such as CHART, 80 mg/kg/day of oral nicotinamide is feasible and clinically tolerated, giving no or few side effects, and a 2-h interval between its oral administration and radiotherapy should achieve effective plasma levels in most patients.
确定接受CHART方案（连续、超分割、加速放疗）并每日给予烟酰胺的患者的烟酰胺药代动力学。目的是建立药代动力学概况及其在重复给药期间的可重复性、分割放疗的最大耐受剂量、该剂量是否能达到足够高的血浆水平以实现放射增敏、烟酰胺与放疗之间的最佳时间间隔以及毒副作用。
使用高效液相色谱法测定11例头颈部和直肠癌晚期患者接受CHART治疗（12天内36次分割）时的烟酰胺血浆浓度。在10例患者中获得了放疗第一天的动力学概况和剩余24小时的值；其中4例在治疗过程中重复进行了两到三次完整的概况测定。在另一例患者中 在12天内每天采集一次样本，共采集4次。每天在第二次放疗分割前90分钟给予80、90或100mg/kg/天的剂量。
所有患者对80mg/kg/天的剂量耐受性良好。然而，剂量增加10 - 25%会导致明显的药物蓄积和严重的临床毒性，剂量递增组中没有患者完成计划的治疗方案。患者间绝对峰值浓度差异很大，范围为0.4至1.4μmol/ml（平均0.9±0.3；标准差（SD））。在五个峰值水平最低的样本中，有四个来自一名患者。达到峰值浓度的时间也非常多变，为0.8至4小时（平均2.1±1.3小时；SD）。在70%的样本中，给药后1 - 2小时内血浆绝对水平≥0.7μmol/ml，并维持长达6小时（平均2.8±1.8小时；SD）。当剂量从80mg/kg增加到90或100mg/kg时，烟酰胺的半衰期有小幅但无显著意义的增加（分别为7.1小时和8.6小时）。
在CHART这样的加速治疗方案中，口服烟酰胺80mg/kg/天是可行的且临床可耐受，副作用少或无，口服给药与放疗之间间隔2小时应能使大多数患者达到有效的血浆水平。
