Search

Purpose: To determine whether tumour radiosensitization and the therapeutic benefit of administering carbogen with nicotinamide depend upon irradiating at the time of peak drug concentration., Materials and Methods: Local tumour control of CaNT tumours in CBA mice and acute skin reactions in albino WHT mice were assessed after treatment with 10 X-ray fractions in air, carbogen alone or combined with 0.1, 0.2 or 0.5 mg g(-1) nicotinamide, injected 15, 30 or 60 min before irradiation. Plasma and tumour drug pharmacokinetics were performed., Results: Nicotinamide was rapidly taken up into tumours; a six- and threefold higher concentration was obtained with 0.5 mg g(-1) compared with 0.1 and 0.2 mg g(-1), respectively. Tumour, but not skin, radiosensitization increased as the dose of nicotinamide increased (p = 0.03), but at each dose level there was no significant difference in radiosensitivity when irradiations were done at or after the time of peak concentration. An almost eightfold increase in plasma levels increased tumour enhancement ratios from 1.74 to 1.92 (p < 0.0001). In tumours all schedules gave significant enhancement relative to carbogen alone (p < or = 0.04)., Conclusions: Tumour and skin radiosensitivity was independent of time of nicotinamide administration. Higher drug concentrations were not mirrored by proportionally higher enhancement ratios. Lower plasma levels than previously suggested significantly enhanced tumour radiosensitivity relative to carbogen alone. The clinical implications of these findings are discussed.

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., Aim: 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.

Background and Purpose: ARCON (Accelerated Radiotherapy, CarbOgen, Nicotinamide) achieves a large therapeutic gain in rodents. A phase I/II study was therefore undertaken to determine its feasibility in patients with locally advanced head and neck cancer., Materials and Methods: The accelerated regime CHART was used in 35 patients given carbogen and/or nicotinamide with 11 small volume fractions. Eight patients received carbogen, 12 received nicotinamide and 15 were treated with ARCON. Treatment compliance, side-effects and acute mucositis were monitored in all cases., Results: All patients underwent CHART as intended. In the 23 patients receiving carbogen, two failed to complete treatment. Compliance with nicotinamide was much lower. Out of 25 patients, only 52% received 10-11 doses of the 80 mg/kg/day of the drug. The most common side-effect was nausea and vomiting, which responded to standard anti-emetics in almost half of the patients. Historical comparisons with the CHART head and neck trials indicate that there was no increase in the severity of acute mucositis in any of these patients. Although the observation period is not sufficiently long to be definitive (median 20 months) there is no evidence of an increase in late normal tissue reactions., Conclusions: ARCON using CHART as the radiotherapy protocol is feasible in patients with advanced head and neck cancer. However, we are concerned about the low compliance rate in our patients, which is far lower than that reported elsewhere. The implications are discussed together with identifying strategies for increasing compliance.

Background and Purpose: Nicotinamide was administered daily as a liquid formulation to head and neck cancer patients receiving a 5- to 7-week course of radiotherapy. The pharmacokinetics, compliance, and tolerance of this drug formulation were studied., Materials and Methods: Blood samples were drawn and nicotinamide levels determined in 40 head and neck cancer patients. On the first treatment day serial samples were obtained followed by daily samples at the time of irradiation during the first and last full weeks of the treatment. Side-effects of nicotinamide were monitored., Results: In all patients peak concentrations greater than 700 nmol/ml could be obtained 0.25-3 h (mean 0.83 +/- 0.73 h) after drug intake. During the first week of treatment plasma levels at the time of irradiation were adequate in 82% of the samples. This decreased to 59% in the last week of treatment which can be partly attributed to reduced compliance. The most important side-effect of nicotinamide was nausea with or without vomiting occurring in 65% of the patients. Severe side-effects were associated with high plasma concentrations over subsequent days. Tolerance improved after a 25% reduction of dose in six of seven patients but plasma levels at the time of irradiation fell below 700 nmol/ml in four out of six of these patients., Conclusions: Peak plasma concentrations above the 700 nmol/ml level were obtained in all patients but these concentrations could not be reproduced during the entire course of the treatment in a significant portion of the subjects. Side-effects of nicotinamide are associated with plasma concentrations and tolerance can be improved by a moderate reduction of dose.

Carbogen and nicotinamide have been evaluated in a phase II study as hypoxia-modifying agents during radical radiotherapy for bladder cancer using a standard daily 20-fraction schedule. Three groups of patients have received (a) nicotinamide alone, given orally in a dose of 80 mg kg(-1) daily with 52.5 Gy in 20 fractions over 4 weeks, (b) carbogen alone, with 50 Gy in 20 fractions over 4 weeks, and (c) carbogen and nicotinamide, with 50-52.5 Gy in 20 fractions over 4 weeks. Ten patients were treated in each group. All patients completed carbogen and radiotherapy as prescribed, but only 45% completed daily nicotinamide over the 4-week treatment period. The end points of this study were acute bowel and bladder morbidity and local control at cystoscopy 6 months after treatment. An expected level of acute bowel and bladder morbidity was seen that reverted to normal in most patients by 12 weeks with no difference between the three treatment groups. Complete response rates at 6 months were seven out of ten (100%) in the nicotinamide alone group, nine out of ten (90%) in the carbogen alone group and seven out of ten (70%) in the carbogen and nicotinamide group. It is concluded that carbogen and nicotinamide may improve the results of daily fractionated radiotherapy in bladder cancer and that further evaluation is required.

The effect of inhibiting gastric acid secretion on nicotinamide pharmacokinetics was studied in five volunteers with the intent of reducing the large variations observed previously in the time to and magnitude of peak plasma concentrations. Plasma levels were determined using a standard high-performance liquid chromatography (HPLC) method after an oral dose of 3 g of nicotinamide either alone or preceded by pretreatment with omeprazole. Suppression of gastric acid production had no significant effect on the rate of uptake or on the peak levels achieved. To bypass gastric acidity, the rectal route was also assessed using a suppository in four volunteers and one patient undergoing radiotherapy. Absorption was slow and variable and much lower plasma levels were observed than after oral dosing. Thus, no improvement in the pharmacokinetics of nicotinamide was observed using either of these two approaches. Parallel estimations were made using a novel and non-invasive method for monitoring nicotinamide pharmacokinetics in saliva. A large and variable fraction of the total amount of nicotinamide-related material in saliva was found to be nicotinic acid, a metabolite not normally found in human plasma. This conversion was inhibited by the use of a chlorhexidine mouthwash, indicating that the oral flora was responsible for its production. The time to peak levels of nicotinamide or of nicotinamide plus nicotinic acid in saliva correlated well with that in plasma. However, peak concentrations for nicotinamide alone were significantly lower than in plasma, and very variable, whereas for nicotinamide plus nicotinic acid saliva levels were 20-30% higher, but more consistent. Although there are some practical difficulties in quantitatively handling saliva, the method is very useful for monitoring nicotinamide pharmacokinetics and for assessment of compliance with nicotinamide treatment.

Inhibitors of adenosine diphosphoribosyl transferase, like nicotinamide, 3-aminobenzamide and other analogues, can inhibit repair of radiation-induced sublethal and/or potentially lethal damage in some in vitro systems. Therefore, we have tested the effect of nicotinamide on repair parameters in vivo in two rodent normal tissues. In skin, the sensitivity to dose fractionation (1, 2, 5 or 10 X-ray fractions in 5 days) was monitored by defining the alpha/beta ratio in the presence or absence of nicotinamide (0.5 mg g-1) in air or carbogen. Pre- and postirradiation sensitization were investigated using an X-ray schedule of 5 fractions/5 days in carbogen alone or combined with nicotinamide given 1 h before, immediately after or 8 h after irradiation. Also, changes in the steepness of the underlying X-ray survival curve for the target skin clonogens, reflected by a change in the alpha/beta ratio, were investigated using the neutron top-up design. Underlying survival curves for oxygen +/- nicotinamide were obtained over the X-ray dose range 2.5 to 25 Gy, by administering single X-ray doses and following these with single top-up doses of d(4)-Be neutrons. Finally, in mouse kidney, recovery half-times (t1/2) were obtained by determining the time-dependent disappearance of X-ray damage using a split-dose design of two 6-Gy fractions separated by an interval which varied from 0 to 48 h and followed by two top-up doses from a neutron beam. No increase in alpha/beta for epidermal damage was seen with nicotinamide alone and, although sensitization was observed when the drug was given 1 h before irradiation, no postirradiation sensitization was detected. In kidney, there was no significant difference in the proportion of total repairable damage or in the half-life of recovery between treatments given with or without nicotinamide. Therefore, no decrease in normal tissue tolerance should be observed with the use of nicotinamide in clinical radiotherapy resulting either from reduced sparing with dose fractionation or from an increase in residual damage when shortening the interfraction interval. Finally, unless repair of radiation damage in normal tissues in vivo differs markedly from that of tumors, it is unlikely that the large sensitization seen in rodent tumors at 1.5 to 2 Gy per fraction, with carbogen and nicotinamide, can be attributed to nicotinamide acting as a repair inhibitor.

The influence of nicotinamide formulation on absorption characteristics and incidence of adverse side-effects has been studied in normal volunteers and in patients undergoing radiotherapy. Escalating single or repeated oral doses of nicotinamide were administered in tablet or liquid form under fasting or non-fasting conditions. Drug absorption was slowed both by the presence of food in the stomach and by the administration of nicotinamide in tablet form compared with when it was dissolved in orange juice. Peak concentrations were generally slightly higher following the liquid preparation, but the incidence of adverse side-effects (chiefly nausea) was increased. A single dose of 9 g (88-97 mg/kg) nicotinamide in tablet form was well tolerated in two fasting normal volunteers, and in patients, doses of up to 133 mg/kg as tablets were tolerated twice/week for three weeks. Daily administration of 80 mg/kg nicotinamide was tolerated when given as tablets, but not in a liquid formulation. Neither the peak concentration nor the area under the concentration/time curve (AUC) of nicotinamide, nor the main metabolites of nicotinamide appeared to correlate with the incidence of toxicity.

Purpose: 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., Methods and Materials: 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., Results: 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)., Conclusions: 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.

Nicotinamide sensitizes murine tumours to the effect of radiation, but the pharmacokinetics are not well characterized at doses that are achievable in humans. In the mouse, nicotinamide given i.p. at doses of 100-500 mg/kg showed biphasic elimination with dose-dependent changes in half-life. The initial half-life increased significantly (P < 0.05) from 0.8 to 2 h and the terminal half-life increased from 3.4 to 5.6 h over the dose range studied. Clearance, however, decreased significantly from 0.3 to 0.24 l kg-1 h-1 only at the highest dose. Peak concentrations increased in a dose-dependent manner from 1,000 to 4,800 nmol/ml. The main plasma metabolite in the mouse is nicotinamide N-oxide, the peak concentration of which increased only from 80 to 160 nmol/ml. The N-oxide, which is also a weak radiosensitizer, is subject to reduction to the parent nicotinamide following administration at a dose of 276 mg/kg; peak concentrations of the N-oxide of 1900 nmol/ml were reached in 10 min, whereas concentrations of nicotinamide produced by reduction reached a maximum of 144 nmol/ml at 1 h. Elimination of the N-oxide was also biphasic, with initial and terminal half-lives being 0.39 and 1.8 h, respectively. The bioavailability of both drugs given via the i.p. as compared with the i.v. route was close to 100%. Tumour concentrations of nicotinamide paralleled those in the plasma after a short lag. Tumour nicotinamide adenine dinucleotide (NAD) concentrations were elevated by factors of 1.5 and 1.8 following doses of 100 and 500 mg/kg nicotinamide, respectively. Maximal concentrations were seen after 3-6 h, but levels remained elevated for 16 h. No change in tumour energy charge or in plasma 5-hydroxytryptamine was detected following a dose of 500 mg/kg nicotinamide.

Combining accelerated radiotherapy with carbogen and nicotinamide (NAM) has been proposed as a strategy to overcome the sparing effect of tumour clonogen repopulation and hypoxia. Six patients with squamous cell carcinomas of the head and neck were given accelerated radiotherapy, carbogen breathing and high dose nicotinamide in order to evaluate the feasibility of this treatment regimen. The patients received radiotherapy in two daily fractions of 1.8-1.9 Gy, five days/week, total dose 54-57.6 Gy, in an overall treatment time of 19-22 days. The interfraction intervals were 7-8 hours between the two fractions on the same day. Carbogen breathing was started 5 minutes before and went on during each radiation fraction. a variety of NAM doses were administered orally in conjunction with radiation therapy and analyses of plasma concentrations of NAM and its metabolites were performed. The most common side-effect from NAM was nausea and vomiting, which in one case hampered further NAM administration. The side effects were not related to plasma levels of NAM or its main metabolites. Additionally, one patient with preexisting heart disease developed a severe hypotension and renal dysfunction. All acute reactions healed without further complications. The mucosal reactions were generally brisk. Thus, the combination of accelerated radiotherapy with carbogen and NAM seems to be tolerable.

Plasma concentrations, after administration of varying doses of nicotinamide, were measured in CBA male mice using a newly-developed high performance liquid chromatography assay. In all dose groups, peak levels were observed within the first 15 min after an i.p. administration of 0.1, 0.2, 0.3 or 0.5 mg g-1 of nicotinamide. There was a clear dose-dependent increase in plasma concentration with increasing dose, with almost a five-fold lower concentration (1.0 vs 4.9 mumol ml-1) achieved with a dose of 0.1 mg g-1 compared with 0.5 mg g-1, respectively. The half-life of nicotinamide increased from 1.4 h to 2.2 h over the dose range (P < 0.01). Comparisons with previous pharmacokinetic data in humans show that clinically-relevant oral doses of 6 and 9 g in humans give plasma levels slightly higher than those achieved at 1 h with doses of 0.1 to 0.2 mg g-1 in mice. Tumour radiosensitisation with carbogen alone, and with carbogen combined with varying doses of nicotinamide (0.05 to 0.5 mg g-1), was investigated using a 10-fraction in 5 days X-ray schedule. Relative to air-breathing mice, a statistically significant increase in sensitisation was observed with both a local tumour control and with an in vivo/in vitro excision assay (P < or = 0.007). With the local control assay, a trend was observed towards lower enhancement ratios (ERs) with decreasing nicotinamide dose (from 1.85 to 1.55); carbogen alone was almost as effective as when combined with 0.1 mg g-1 of nicotinamide. With the excision assay, ERs for carbogen combined with nicotinamide increased with decreased levels of cell survival. At a surviving fraction of 0.02, enhancement ratios of 1.39-1.48 were obtained for carbogen plus 0.1 to 0.3 mg g-1 of nicotinamide. These were lower than those seen with the two higher doses of 0.4 to 0.5 mg g-1 (ERs = 1.63-1.69).

A high-performance liquid chromatographic method is described which enables the determination of nicotinamide and eight of its possible metabolites in human and murine plasma and urine, using ion-pairing on a base-deactivated reversed-phase column. Calibration curves were linear up to 2 mumol/ml for nicotinamide and 200 nmol/ml for the metabolites; both the intra- and inter-assay relative standard deviations ranged between 1 and 8%. In murine plasma, the N-oxide was the major nicotinamide metabolite, but in man, formation of 1-methylnicotinamide and the 2- and 4-pyridones was also significant. In urine, nicotinuric acid was seen in the mouse, but no nicotinic acid metabolites were seen in man.

The pharmacokinetics of nicotinamide were studied in four human volunteers after oral doses of 1-6 g. Plasma concentrations and clearance rates of the vitamin were found to be dose-dependent, with a half-life of approximately 7-9 h for the two highest doses administered (4 and 6 g), approximately 4 h with 2 g and approximately 1.5 h with a 1-g dose. Peak concentrations ranged from 0.7 to 1.1 mumol.ml-1 after a 6-g dose. The time to reach peak plasma concentration was dose independent with a broad range from 0.73 to 3 h. In this study, nicotinamide had no detectable effect on blood pressure, pulse or body temperature.