CUMULATIVE PHARMACOKINETIC STUDY OF OXALIPLATIN, ADMINISTERED EVERY 3WEEKS, COMBINED WITH 5-FLUOROURACIL IN COLORECTAL-CANCER PATIENTS

The cumulative pharmacokinetic pattern of oxaliplatin, a new diamminec yclohexane platinum derivative, was studied in patients with metastati c colorectal cancer. Oxaliplatin was administered by i.v. infusion (13 0 mg/m(2)) over 2 h every 3 weeks, and 5-fluorouracil and leucovorin w ere administered weekly, A very sensitive method, inductively coupled plasma-mass spectrometry, allowed for the determination of total plasm a and ultracentrifugable (UC) and RBC platinum levels on day 1, at 0, 2, and 5 h, and on days 8, 15, and 22, Sixteen patients underwent thre e or more courses, and six of them underwent six or more courses, The platinum concentration curves were quite similar from one course to an other, with a high peak value 2 h after administration (day 1, C-max = 3201 +/- 609 mu g/liter) and a rapid decrease (day 8, 443 +/- 99 mu g /liter). C-max of both total and UC platinum levels in plasma remained unchanged throughout the treatment, The mean total platinum half-life in plasma was 9 days, We found residual levels of total platinum on d ay 22 (161 +/- 45 mu g/liter), but we observed no significant accumula tion for the four first cycles (P = 0.57), In contrast, platinum accum ulated significantly in RBCs after three courses (+91% at day 22 of th e third cycle versus day 22 of the first cycle, P = 0.000018), and its half-life there was equivalent to that of RBCs, The patterns of UC an d total platinum concentration curves were very similar and correlated significantly (P < 10(-6)) at all sampling times, The mean UC:total p latinum ratio was 15% at day 1 and 5% at days 8, 15, and 22 in the 3-w eek treatment course, Unlike cisplatin, which rapidly accumulates in p lasma as both free and bound platinum, oxaliplatin does not accumulate in plasma, but it does accumulate in RBCs, after repeated cycles at t he currently recommended dose (130 mg/m(2)) and schedule of administra tion (every 3 weeks).