Clinical pharmacokinetic and in vitro combination studies of nolatrexed dihydrochloride (AG337, Thymitaq) and paclitaxel.

摘要: A clinical study of nolatrexed dihydrochloride (AG337, Thymitaq(TM)) in combination with paclitaxel was performed. The aims were to optimize the schedule administration and determine any pharmacokinetic (PK) interactions between two drugs. In vitro studies performed assist optimization. Three patients entered on each three different schedules drugs: (1) 0-3 h, 24-144 h; (2) 0-120 48-51 (3) 126-129 h. Paclitaxel administered at a dose 80 mg m(-2) over 3 h 500 day(-1) as 120-h continuous intravenous infusion. Plasma concentrations both drugs determined by high performance liquid chromatography. growth inhibition using corresponding head neck cancer cell lines. HNX14C HNX22B lines, synergistic observed 2, whereas 1 demonstrated antagonistic effects. study, there no effect pharmacokinetics nolatrexed. However, had higher clearance (322-520 mi min(-1) m(-2)) than those 2 (165-238 m(-2)). Peak plasma (1.66-1.93 vs 0.86-1.32 mu M) areas under curve (392-565 180-291 M min(-1)) correspondingly 2. interaction confirmed human liver microsomes, being an inhibitor major routes metabolism paclitaxel. Toxicity not schedule-dependent. Nolatrexed may be safely given together when sequentially doses used this study. Studies suggest some synergy, however, due interaction, should reduced during (C) 2000 Cancer Research Campaign.