Pharmacokinetics of nicotinamide in cancer patients treated with accelerated radiotherapy: the experience of the Co-operative Group of Radiotherapy of the European Organization for Research and Treatment of Cancer.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Bernier
J
J
Cantonal Department of Radiation Oncology, San Giovanni Hospital, Bellinzona, Switzerland.
Stratford
M R
MR
Denekamp
J
J
Dennis
M F
MF
Bieri
S
S
Hagen
F
F
Kocagöncü
O
O
Bolla
M
M
Rojas
A
A
D000284:Administration, Oral; D019540:Area Under Curve; D002245:Carbon Dioxide / Q000493:pharmacokinetics / Q000627:therapeutic use; D002277:Carcinoma / Q000532:radiotherapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000532:radiotherapy; D015687:Cell Hypoxia / Q000187:drug effects; D019583:Dose Fractionation, Radiation; D005500:Follow-Up Studies; D006207:Half-Life; D006258:Head and Neck Neoplasms / Q000532:radiotherapy*; D006801:Humans; D008175:Lung Neoplasms / Q000532:radiotherapy*; D009325:Nausea / Q000139:chemically induced; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010100:Oxygen / Q000493:pharmacokinetics / Q000627:therapeutic use; D011728:Pyridones / Q000097:blood; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013607:Tablets; D013997:Time Factors; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
D011728:Pyridones; D011838:Radiation-Sensitizing Agents; D013607:Tablets; D002245:Carbon Dioxide; D009536:Niacinamide; C037645:nicotinamide N-oxide; C011700:carbogen; D010100:Oxygen; C024058:N(1)-methylnicotinamide