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

A clinical study of nolatrexed dihydrochloride (AG337, Thymitaq(TM)) in com bination with paclitaxel was performed. The aims were to optimize the sched ule of administration and determine any pharmacokinetic (PK) interactions b etween the two drugs. In vitro combination studies were performed to assist with schedule optimization. Three patients were entered on each of three d ifferent schedules of administration of the two drugs: (1) paclitaxel 0-3 h , nolatrexed 24-144 h; (2) nolatrexed 0-120 h, paclitaxel 48-51 h; (3) nola trexed 0-120 h, paclitaxel 126-129 h. Paclitaxel was administered at a dose of 80 mg m(-2) over 3 h and nolatrexed at a dose of 500 mg m(-2) day(-1) a s a 120-h continuous intravenous infusion. Plasma concentrations of both dr ugs were determined by high performance liquid chromatography. in vitro gro wth inhibition studies using corresponding schedules were performed using t wo head and neck cancer cell lines. In both HNX14C and HNX22B cell lines, s ynergistic growth inhibition was observed on schedule 2, whereas schedules 1 and 3 demonstrated antagonistic effects. In the clinical study, there was no effect of schedule on the pharmacokinetics of nolatrexed. However, pati ents on schedules 1 and 3 had a higher clearance of paclitaxel (322-520 mi min(-1) m(-2)) than those on schedule 2 (165-238 mi min(-1) m(-2)). Peak pl asma concentrations (1.66-1.93 vs 0.86-1.32 mu M) and areas under the curve (392-565 vs 180-291 mu M min(-1)) of paclitaxel were correspondingly highe r on schedule 2. The pharmacokinetic interaction was confirmed by studies w ith human liver microsomes, nolatrexed being an inhibitor of the major rout es of metabolism of paclitaxel. Toxicity was not schedule-dependent. Nolatr exed and paclitaxel may be safely given together when administered sequenti ally at the doses used in this study. Studies in vitro suggest some synergy , however, due to a pharmacokinetic interaction, paclitaxel doses should be reduced when administered during nolatrexed infusion. (C) 2000 Cancer Rese arch Campaign.