Influence of oxaliplatin on 5-fluorouracil plasma clearance and clinical consequences.
The influence of oxaliplatin (OXA) on 5-fluorouracil (5-FU) plasma clearance was investigated.


METHODS
A group of 29 patients with advanced colorectal cancer refractory to prior weekly 8-h 5-FU infusion plus bolus folinic acid (FA), received the same combination plus OXA at 130 mg/m(2) every 3 weeks, OXA plus 5-FU plus FA on day 1, and 5-FU plus FA on days 8 and 15. Steady-state 5-FU concentrations in plasma were measured weekly and 5-FU clearance was calculated. Both before and after the addition of OXA, the 5-FU dose was individually adjusted according to the pharmacokinetic follow-up (target steady-state plasma concentrations 2.5-3 mg/l).


CONCLUSIONS
A total of 122 OXA-containing infusions and 338 5-FU plus FA infusions were given and the median number of infusions per patient was 4 (2-9) and 10 (5-28), respectively. 5-FU plasma clearance was significantly decreased on days 8 and 15 when compared with the value on day 1 and with the values before OXA introduction using a direct paired comparison (2.36 and 2.31 l/min, respectively, vs 3.12 and 3.05 l/min; P<10(-5)). Of 25 evaluable patients, 6 had an objective response after the introduction of OXA (24% objective response rate, 95% confidence interval 9.4-45%).


CONCLUSIONS
OXA reduces 5-FU plasma clearance for 15 days. This may be a factor in the synergy between the two drugs. It is not linked to dihydropyrimidine dehydrogenase inhibition. Implications for drug schedules in clinical practice are discussed.
Boisdron-Celle
M
M
Department of Medical Oncology and Clinical Pharmacology, Centre Paul Papin, Centre Régional de Lutte Contre le Cancer, 49000 Angers cedex, France.
Craipeau
C
C
Brienza
S
S
Delva
R
R
Guérin-Meyer
V
V
Cvitkovic
E
E
Gamelin
E
E
D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D000077150:Oxaliplatin; D012004:Rectal Neoplasms / Q000188:drug therapy
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D005472:Fluorouracil