PHARMACOKINETICS OF NICOTINAMIDE IN CANCER-PATIENTS TREATED WITH ACCELERATED RADIOTHERAPY - THE EXPERIENCE OF THE COOPERATIVE-GROUP-OF-RADIOTHERAPY OF THE -ORGANIZATION-FOR-RESEARCH-AND-TREATMENT-OF-CANCER

Background: The EORTC has initiated studies to combine nicotinamide wi th carbogen in accelerated fractionation schedules (ARCON), since for some tumour types, acute and chronic hypoxia as well as treatment prot raction may prejudice the outcome of radiotherapy. The tolerable dose of nicotinamide and the optimal interval for administration need to be ascertained. Aim: Full pharmacokinetic profiles of nicotinamide conce ntrations in plasma were analyzed repeatedly in 15 patients to determi ne the inter- and intra-patient variability in peak plasma concentrati ons and the optimum times for administering nicotinamide as a radiosen sitizer. Methods: Nicotinamide (Nicobion(R)) was administered in table t 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 a fter an overnight fast and at least 30 min before breakfast. In 15 pat ients, 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 o n two to four occasions for the head and neck cancer patients and on t wo occasions for the lung cancer patients. For each profile, the maxim um concentration of nicotinamide (C-max), time to peak plasma concentr ation (T-max), elimination half-lives (t(1/2)) and area under the curv e (AUC) were determined. Compliance was recorded and nausea and vomiti ng were graded on a 0-3 scale. Complete profiles of the five major met abolites were also obtained. Results: In the 48 complete sets of blood samples, peak plasma concentrations ranged from 787 to 2312 nmol/ml w ith a median value of 1166 nmol/ml. The peak plasma concentration was achieved at 1 h in only 54% of the pharmacokinetic profiles, bur at th is time 92% of the profiles had already exceeded the target concentrat ion of 700 nmol/ml, the level required in the mouse for tumour radiose nsitization. The median t(1/2) for all 15 cases was 9.3 h, with minimu m 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 an d found not to be correlated with any of the pharmacokinetic parameter s. Conclusions: The plasma concentrations considered necessary to radi osensitize 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 appar ently would have been achieved in most even with a considerable reduct ion in dose. An adequate time between administration and radiotherapy appeared to be 1 h with this drug formulation for 92% of the profiles. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.