Pharmacokinetics of trimetrexate administered by five-day continuous infusion to patients with advanced cancer

Abstract

The disposition of the methotrexate analogue trimetrexate (TMTX, NSC 352122; 2,4-diammino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]qui nazoline) was determined in a Phase I study in 16 patients with refractory or relapsing cancer. The drug was administered by continuous 5-day infusion at doses of 5 to 60 mg/m2/120 h (1-12 mg/m2 daily for 5 days). Plasma and urine collections were made during and after infusion and TMTX levels were quantitated by a specific and sensitive high-performance liquid chromatographic assay. Estimates of pharmacokinetic parameters were similar when determined by either compartmental or noncompartmental methods. There were no significant differences in parameters between the first and second courses of treatment to 10 of the patients. Significant linear relations between TMTX dose and the area under curve of plasma TMTX (r2 = 0.858, P = 0.0001) and the steady-state TMTX plasma level (r2 = 0.764, P = 0.0001) were established. Total TMTX clearance was 30.4 +/- 7.6 (SD) ml/min/m2, renal clearance 7.80 +/- 3.9 ml/min/m2, nonrenal clearance 23.2 +/- 7.1 ml/min/m2, volume of distribution 32.8 +/- 16.6 liters/m2, and terminal half-life 13.4 +/- 7.0 h. The percentage of the trimetrexate dose excreted unchanged in urine ranged from 8.4 to 40.7% (mean, 24.9 +/- 9.2%) and was related to creatinine clearance (r2 = 0.312, P = 0.010). Trimetrexate renal clearance was also related to urine flow (r2 = 0.330, P = 0.008). Trimetrexate pharmacokinetics was linear over the dose range 5 to 60 mg/m2 when given by 5-day continuous infusion to patients but there was evidence of urine flow-dependent renal clearance which requires further examination.