Phase I studies with the nonclassical antifolate nolatrexed dihydrochloride (AG337, THYMITAQ) administered orally for 5 days

Phase I studies of p.o. administered nolatrexed dihydrochloride (AG337, THY MITAQ), a nonclassical thymidylate synthase inhibitor, were performed to es tablish the maximum tolerated dose and a recommended dose for Phase II stud ies. The bioavailability and pharmacokinetic and pharmacodynamic properties of oral nolatrexed were also studied. Forty-five patients were treated wit h oral nolatrexed every 6 h for 5 days at doses of 288-1000 mg/m(2)/day, Th e bioavailability of the oral preparation was determined, and the effect of a standard meal on nolatrexed absorption was investigated at a dose of 800 mg/m(2)/day. Nolatrexed plasma concentrations were analyzed by high-perfor mance liquid chromatography, Nolatrexed was rapidly absorbed with a median bioavailability of 89% (range 33-116%), with 88% of patients above 70%. The dose-limiting toxicities were gastrointestinal, and the recommended Phase II oral dose was 800 mg/m(2)/day. After a standard meal, the peak plasma no latrexed concentration achieved was lower (median, 8.3 mu g/ml versus 15.0 mu g/ml; P = 0.001), and the time taken to reach the peak was longer (media n, 180 min versus 45 min; P = 0.00003), but the trough concentration was hi gher (median, 3.6 mu g/ml versus 2.1 mu g/ml; P = 0.004) when compared with the fasted state. The area under the nolatrexed plasma concentration versu s time curve was not affected by food. Average trough nolatrexed concentrat ion, but not dose, was significantly related to the % decrease in both thro mbocytes (r(2) = 0.58; C-50 = 6.0 mu g/ml, where C-50 is the plasma concent ration associated with a 50% decrease in thrombocytes) and neutrophils (r(2 ) = 0.63; C-50 = 0.6 mu g/ml). Nolatrexed can be safely administered as an oral preparation at a dose of 800 mg/m(2)/day for 5 days. Bioavailability w as close to 100% and, because inhibition of thymidylate synthase by nolatre xed is rapidly reversible, the slower absorption after a standard meal may result in a shorter duration of noninhibitory concentrations between doses.