Pharmacokinetics of dacarbazine (DTIC) and its metabolite 5-aminoimidazole-4-carboxamide (AIC) following different dose schedules

Abstract

The pharmacokinetics of dacarbazine (DTIC) and its main metabolite 5-aminoimidazole-4-carboxamide (AIC) have been studied in eight patients with malignant melanoma or sarcoma receiving 2.65--6.85 mg DTIC/kg body weight by intravenous bolus injection or by continuous 0.5--6-h infusions on 5 consecutive days. The plasma disappearance of DTIC was biphasic, with a terminal half-life of 41.4 min (range 30.3--51.6 min). The mean distribution volume of DTIC was 0.632 liters/kg and the total clearance was 15.4 ml/kg . min (range 8.7--23.3 ml/kg . min). The renal clearance of DTIC was 5.2--10.9 ml/kg . min, indicating that about 50% of DTIC was eliminated by extrarenal mechanisms. The plasma decay of AIC was mono-exponential with a half-life of 43.0--116 min. A renal clearance of 2.6--5.3 ml/kg . min was calculated for AIC. The urinary recovery was 46%--52% for DTIC and 9%--18% for AIC. The plasma concentrations of DTIC observed during 0.5--6-h infusions of DTIC (5.45--6.85 mg/kg) were 0.66--6.2 micrograms/ml. Comparison of various dosage schedules within the same patient did not reveal relevant differences of the areas under the concentration-time curves. Immunotherapy with Bacillus Calmette-Guérin (BCG) did not significantly influence the pharmacokinetics of DTIC. During isolated extremity perfusion with DTIC (75--130 mg/kg extremity) for treatment of malignant tumors of the extremities concentrations of DTIC ranged from 150--500 micrograms/ml perfusate. There was no evidence of AIC formation. In isolated liver perfusion experiments in anesthetized dogs metabolic degradation of DTIC to AIC was demonstrated.

A phase 1‐2 study of imexon plus dacarbazine in patients with unresectable metastatic melanoma

“…For dacarbazine and the AIC metabolite, the current results are comparable to prior studies from Breithaupt et al 22 and Rajkumar et al 23 The dacarbazine half-life ranged from 30 to 52 minutes (mean, 41.4 minutes) in the study by Breithaupt et al, 22 compared with 19 to 59 minutes (mean, 51.3 minutes) in the current study. The mean peak dacarbazine plasma level of 6.1 lg/mL for a 30-minute infusion of 250 mg/m 2 in the current study compares to peak levels in the study by Breithaupt et al of 6.85 lg/mL for a dose-normalized 2.65-mg/kg dose given as an intravenous bolus.…”

“…Table 4 shows the pharmacokinetic parameters of imexon, dacarbazine, and its metabolite AIC in patients receiving 1000 mg/m 2 of imexon administered as 30-or 45-minute infusions followed by 250 mg/m 2 dacarbazine administered as a 30-or 45-minute infusion. When the pharmacokinetic parameters for dacarbazine in this study were compared with those previously published, 22,23 there were no differences in any of the parameters, so it was concluded that the administration of imexon was unlikely to have altered the pharmacokinetics of dacarbazine.…”

Development of nanostructured lipid carrier for dacarbazine delivery

“…The only formulation of Dac in clinical use is given by intravenous infusion with drug half-life less than 1 h [11].…”

“…The only available formulation for clinical use is delivered through intravenous injection. After injection at 2.6-6.8 mg/body weight, the plasma concentration of the drug reached 6 lg/mL with half-life around 41 min [11]. A single-dose of 850-1000 mg/m [2] administered once every 3 weeks was referenced as standard therapy with response rate of 13-20 % of patients [12][13][14].…”

Dosage and cycle effects of dacarbazine (DTIC) and fotemustine on O6-alkylguanine-DNA alkyltransferase in human peripheral blood mononuclear cells

“…This suggests that the pharmacokinetics of DTIC is dose-dependent. Indeed, it has been shown that high-dose DTIC (850-1980 mg m-2) follows nonlinear pharmacokinetics with saturation occurring in the metabolism and also a slower distribution and disposition rate when compared to lower dose DTIC (Breithaupt et al, 1982;Buesa & Urrechaga, 1991;Loo et al, 1968;Skibba et al, 1969). The later nadir in ATase activity seen with 800 mg m-2 DTIC in contrast to 400 mg m2 may be related to the more protracted production of alkylating metabolites.…”