PHARMACOKINETICS OF CISPLATIN IN COMBINED CISPLATIN AND 5-FLUOROURACIL THERAPY - A COMPARATIVE-STUDY OF 3 DIFFERENT SCHEDULES OF CISPLATIN ADMINISTRATION

Background: Cisplatin is widely used in combination chemotherapy again st a variety of tumors; however, the optimal administration schedule o f cisplatin is still controversial. To clarify the pharmacokinetic dif ferences according to the administration schedules of cisplatin, we co mpared three different administration schedules of cisplatin such as s ingle short-term infusion, daily short-term infusion and daily continu ous infusion in combination with 5-fluorouracil. Preliminary clinical responses and toxicities were also investigated. Methods: A total of 1 2 courses in combination of cisplatin and 5-fluorouracil therapy was s tudied. The schedules of cisplatin tested were as follows: single shor t-term infusion (80 mg/m(2), day 1, 2 h div., n = 4), daily short-term infusion (20 mg/m(2), days 1 to 5, 2 h div., n = 4), daily continuous infusion (100 mg/m(2), 120 h, n = 4). In all schedules, 5-fluorouraci l was continuously administered at a dose of 800 mg/m(2)/day on days 1 to 5. The area under the time-concentration curve (AUC) and the maxim um concentration (C-max) of total and free Pt were investigated. Resul ts: The highest AUC of total acid free Pt and the lowest C-max of free Pt were observed in the daily continuous infusion (total AUG; 162.53 +/- 18.39 mu g h/ml, free AUG; 5.50 +/- 0.9 mu g h/ml, free C-max; 0.0 7 +/- 0.01 mu g/ml, mean +/- SEM). Two patients in the single short-te rm infusion and one patient in the daily continuous infusion indicated partial responses clinically. No nephrotoxicity or ototoxicity was ob served. All toxicities were mild and tolerable in all regimens; howeve r, the incidence of GI toxicity in daily continuous infusion seemed to be relatively higher. Conclusions: Daily continuous infusion of cispl atin gave the best pharmacokinetic results and to evaluate the clinica l advantage of this schedule a prospective randomized trial should be conducted with sufficient numbers of patients.