Cumulative pharmacokinetic study of oxaliplatin, administered every three weeks, combined with 5-fluorouracil in colorectal cancer patients.
The cumulative pharmacokinetic pattern of oxaliplatin, a new diamminecyclohexane platinum derivative, was studied in patients with metastatic colorectal cancer. Oxaliplatin was administered by i. v. infusion (130 mg/m2) over 2 h every 3 weeks, and 5-fluorouracil and leucovorin were administered weekly. A very sensitive method, inductively coupled plasma-mass spectrometry, allowed for the determination of total plasma 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 three or more courses, and six of them underwent six or more courses. The platinum concentration curves were quite similar from one course to another, with a high peak value 2 h after administration (day 1, Cmax = 3201 +/- 609 microgram/liter) and a rapid decrease (day 8, 443 +/- 99 microgram/liter). Cmax 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 day 22 (161 +/- 45 microgram/liter), but we observed no significant accumulation for the four first cycles (P = 0.57). In contrast, platinum accumulated significantly in RBCs after three courses (+91% at day 22 of the 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 and total platinum concentration curves were very similar and correlated significantly (P < 10(-6)) at all sampling times. The mean UC:total platinum ratio was 15% at day 1 and 5% at days 8, 15, and 22 in the 3-week treatment course. Unlike cisplatin, which rapidly accumulates in plasma as both free and bound platinum, oxaliplatin does not accumulate in plasma, but it does accumulate in RBCs, after repeated cycles at the currently recommended dose (130 mg/m2) and schedule of administration (every 3 weeks).
Gamelin
E
E
Department of Medical Oncology and Clinical Pharmacology, Centre Paul Papin, Centre Regional de Lutte Contre le Cancer, 49033 Angers Cedex.
Bouil
A L
AL
Boisdron-Celle
M
M
Turcant
A
A
Delva
R
R
Cailleux
A
A
Krikorian
A
A
Brienza
S
S
Cvitkovic
E
E
Robert
J
J
Larra
F
F
Allain
P
P
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005472:Fluorouracil / Q000008:administration & dosage; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage / Q000627:therapeutic use; D013058:Mass Spectrometry; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000077150:Oxaliplatin; D010984:Platinum / Q000097:blood; D012044:Regression Analysis; D012680:Sensitivity and Specificity
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010984:Platinum; D002955:Leucovorin; D005472:Fluorouracil