ADMINISTRATION OF NICOTINAMIDE DURING CHART - PHARMACOKINETICS, DOSE-ESCALATION, AND CLINICAL TOXICITY

Purpose: To determine nicotinamide pharmacokinetics in patients underg oing accelerated radiotherapy with the CHART regimen (continuous, hype rfractionated, accelerated radiotherapy) and given nicotinamide on a d aily basis. The aim was to establish the pharmacokinetic profiles and their reproducibility during repeated administration, the maximum tole rated dose with fractionated radiotherapy, whether such a dose achieve s sufficiently high plasma levels for radiosensitization, the optimal time interval between nicotinamide and irradiation, and toxic side eff ects. Methods and Materials: Nicotinamide plasma concentrations were d etermined 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 d ay of radiotherapy and residual 24-h values were obtained in 10 patien ts; in four of these, full profiles were repeated two or three times d uring the course of treatment. In one other, a single sample per day w as 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. Results: A dose of 80 mg/kg/day was well tolerated by all t he patients. However, an increase of 10-25% in dose led to significant drug accumulation and major clinical toxicity, and none of the patien ts in the dose-escalation arm completed the planned regimen. Large int erpatient variations in absolute peak concentrations were seen from 0. 4 to 1.4 mu mol/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, absol ute plasma levels greater than or equal to 0.7 mu mol/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 th e 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). Conclusions: In an accel erated regimen such as CHART, 80 mg/kg/day of oral nicotinamide is fea sible and clinically tolerated, giving no or few side effects, and a 2 -h interval between its oral administration and radiotherapy should ac hieve effective plasma levels in most patients.