Pharmacokinetics and pharmacodynamic effects of 5-fluorouracil given as a one-hour intravenous infusion

Purpose: Clinical toxicity associated with 5-fluorouracil (5-FU) is related to the area under the plasma concentration-time curve (AUC). Recently, sho rt-term infusions of 5-FU given over 30 or 60 min have been substituted for conventional "bolus" 5-FU given over 3-5 min in randomized clinical trials , but there are only limited pharmacokinetic data for these altered infusio n durations. We therefore wished to determine the pharmacokinetics and toxi city associated with 5-FU given as a 1-h intravenous (i.v.) infusion. Metho ds: A group of 22 adults with advanced gastrointestinal tract cancers and n o prior systemic chemotherapy for advanced disease received interferon alph a -2a (5 MU/m(2) s.c., days 1-7), leucovorin (500 mg/m(2) i.v. over 30 min, days 2-6) and 5-FU (370 mg/m(2) i.v. over 1 h, days 2-6). The doses of 5-F U and interferon-a were adjusted according to individual tolerance. The pha rmacokinetics and clinical toxicity were retrospectively compared with pati ents receiving the same regimen under the same treatment guidelines except that 5-FU was given over 5 min. Results: The regimen was well tolerated, an d 41% of the patients tolerated 5-FU dose escalations to 425-560 mg/m(2) pe r day. Grade 3 or worse diarrhea and fatigue ultimately occurred in 14% of the patients each. Granulocytopenia, mucositis, and diarrhea appeared to be appreciably milder in the present trial compared with our prior phase II e xperience in colorectal cancer. The peak 5-FU plasma levels and AUC with 37 0 mg/m2 5-FU given over 1 h were 7.3-fold and 2.4-fold lower than previousl y measured in 31 patients who received 5-FU over 5 min. Conclusion: Increas ing the length of 5-FU infusion to 1 h seemed to substantially reduce the c linical toxicity with this modulated 5-FU regimen, likely due to markedly l ower peak 5-FU plasma levels and AUG. Changes in the duration of a short in fusion of 5-FU clearly affects the clinical toxicity, but raises the concer n of a potentially adverse impact on its antitumor activity, These results suggest the importance of including precise guidelines concerning the time over which 5-FU is given in clinical trials. Having a specified duration of 5-FU infusion is also important if 5-FU dose escalation is considered.