Pharmacokinetic study of trimetrexate in combination with cisplatin

The addition of the antifol methotrexate to cisplatin (DDP) produces supraadditive antitumor effects in preclinical studies, but in the clinic this combination of two nephrotoxic drugs is limited by excessive toxicity. Trimetrexate (TMTX) is a second generation antifol with predominantly nonrenal elimination and antitumor activity superior to that of methotrexate in preclinical models. In early clinical trials TMTX demonstrated promising activity in non-small cell lung cancer, and nephrotoxicity was rare. We performed a Phase I clinical and pharmacological study of TMTX (escalating doses) in combination with DDP (20 mg/m2), both administered i.v. for 5 consecutive days, every 4 wk. The pharmacokinetics of TMTX was determined in 15 patients after administration of the single agent (baseline study) and following the Day 1 and Day 5 doses in the TMTX-DDP combination. The recommended Phase II single-agent dose of TMTX on this schedule, 8 mg/m2, did not produce excessive toxicity when given concurrently with DDP. Significant drug-related nephrotoxicity was not observed, even in patients receiving multiple courses of TMTX-DDP. The mean renal clearance of TMTX increased 1.4-fold and 2.8-fold over baseline on Days 1 and 5, respectively, of TMTX-DDP. Urinary flow was similarly greater on days of TMTX-DDP treatment. The nonrenal clearance of TMTX was unaffected by concurrent DDP. The steady-state volume of distribution, Vdss, and terminal elimination half-life were significantly greater on Day 5 of TMTX-DDP compared to baseline. The plasma protein-binding of TMTX in vitro was not altered by DDP, and the disappearance of ultrafilterable DDP from normal plasma in vitro was unchanged by TMTX. Although a protein-binding interaction of TMTX and DDP was not detected in normal plasma in vitro, the changes in renal clearance, Vdss, and the terminal half-life were consistent with a greater fraction of unbound TMTX in plasma following Day 5 of TMTX-DDP. Effects of DDP on the binding of TMTX to extravascular tissue components, or on the renal handling of TMTX, cannot be excluded. The increase in TMTX renal clearance correlated with increased urinary flow, which may improve the therapeutic index of TMTX as both an antineoplastic and antiparasitic agent.