PHARMACOKINETICS OF HIGH-DOSE METHOTREXATE IN ADULT OSTEOGENIC-SARCOMA

The pharmacokinetics of 222 infusions of high-dose methotrexate (MTX) with leucovorin rescue were studied in 22 adults with osteosarcoma. To reduce the variability of plasma concentration, we individualized dos e regimens using a Bayesian method to reach a concentration of 10(-3) M MTX at the end of an 8-h infusion, The mean concentration observed a t the end of the infusion was 1016+/-143 mu mol/l. The mean dose deliv ered was 13.2+/-2 g/m(2). The clearance was 49.1+/-11.7 ml min(-1) m(- 2) The decay of the plasma concentration of MTX after completion of th e infusion followed a two-compartment model with a t(1/2 alpha) Of 2.6 6+/-0.82 h and a t(1/2 beta) of 15.69+/-8.63 h. The volume of distribu tion was 0.32+/-0.08 l/kg. As compared with previously published data, the interindividual and intraindividual variations in the concentrati on at the end of the infusion were reduced, with values of 14% and 5.9 %-21%, respectively, being obtained. Severe toxicities were avoided, a nd there were only 3 hematologic and 8 digestive grade 3 side effects and no grade 4 complication. The t(1/2 alpha) and the MTX plasma conce ntrations at 23 and 47 h were correlated with renal toxicity (P < 0.00 1). However, no correlation was found between the pharmacokinetic para meters and other signs of toxicity. There was no significant differenc e in pharmacokinetics between the toxic and nontoxic groups. In the sa me manner, the parameters of the group of patients sensitive to MTX we re not statistically significantly different from those of the group o f nonsensitive patients.