Clinical pharmacokinetics of high-dose DTIC

Abstract

The pharmacokinetics of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC, dacarbazine) given at a dose of 850-1,980 mg/m2 as a 10- to 30-min infusion was studied in cancer patients, and the plasma concentration-time curves were adjusted to a two-compartment model, with a mean t1/2 alpha value of 0.17 h (range, 0.1-0.26 h) and a mean t1/2 beta value of 2 h (range, 1.5-2.7 h) being found. The mean volume of the central compartment of (Vc) and the apparent volume of distribution (VB) were 0.42 1 kg-1 (range, 0.24-0.54 1 kg-1) and 1.49 1 kg-1 (range, 0.88-1.74 1 kg-1), respectively. The mean total body clearance of DTIC was 0.58 1 kg-1 h-1 (range, 0.26-0.82 1 kg-1 h-1), and the mean renal clearance was 0.28 1 kg-1 h-1 (range, 0.17-0.49 1 kg-1 h-1). Unchanged DTIC recovered from urine within 24 h varied from 11% to 63% of the delivered dose, with an inverse correlation being found between the DTIC dose and the amount excreted. The metabolite aminoimidazole carboxamide (AICA) was detectable in plasma from the start of DTIC infusion, and its concentration-time curve showed a monophasic decay, exhibiting a mean t1/2 value of 3.25 h (range, 1.77-5.82 h). Mean AICA renal clearance was 0.15 1 kg-1 h-1 (range, 0.05-0.32 1 kg-1 h-1). The amount of AICA excreted in urine increased with increasing DTIC dose and varied from 1.2% to 13.6% of the delivered DTIC dose. Both DTIC distribution and disposition and AICA production and renal excretion seemed to be limited after high DTIC doses as compared with the pharmacokinetics of low-dose DTIC. Nonlinear pharmacokinetics for high-dose DTIC could not be clearly excluded.