Pharmacokinetics of 5-fluorouracil (5FU) have been related to toxicity and antitumor activity, in particular for continuous infusion schedules, but to a lesser extent for frequently used bolus injections. The use of intensive sampling schedules limits the application of pharmacokinetics to optimize individual dosing or to define the ideal combination with other drugs. We therefore reanalyzed a pharmacokinetic study in order to develop a limited sampling schedule. Patients received escalating doses of 5FU at 500, 600 and 720 mg/m2 as a bolus until toxicity developed. Blood samples were analysed until 24 hr after administration. The area under the concentration time curve from 0-90 min (AUC0-90) strongly correlated with dose and also with toxicity (p = 0.0009). The 5FU concentrations at 30 and 60 min were correlated to the AUC30-240 and to that of AUC0-90 (r2= 0.970). Use of limited sampling (30, 60, 90 min) in a patient given 353 mg/m2 5FU with severe toxicity at initial dosing at 500 mg/m2 revealed that the AUC0-90 at 353 mg/m2 was higher than the normal AUC0-90 for 500 mg/m2. This patient appeared to have an 8-fold lower activity of the 5FU degradation enzyme dihydropyrimidine dehydrogenase. Limited sampling will allow to define potential aberrant kinetics of pharmacokinetic interaction of 5FU with other drugs being developed for treatment of colorectal cancer.
PHARMACOKINETICS OF BOLUS 5-FLUOROURACIL: RELATIONSHIP BETWEEN DOSE, PLASMA CONCENTRATIONS, AREA-UNDER-THE-CURVE AND TOXICITY / CODACCI PISANELLI, Giovanni; Pinedo, Hm; Lankelma, J; VAN GROENINGEN, Cj; VAN KUILENBURG, Ab; VAN GENNIP, Ah; Peters, Gj. - In: JOURNAL OF CHEMOTHERAPY. - ISSN 1120-009X. - 17:(2005), pp. 315-320.
PHARMACOKINETICS OF BOLUS 5-FLUOROURACIL: RELATIONSHIP BETWEEN DOSE, PLASMA CONCENTRATIONS, AREA-UNDER-THE-CURVE AND TOXICITY.
CODACCI PISANELLI, Giovanni;
2005
Abstract
Pharmacokinetics of 5-fluorouracil (5FU) have been related to toxicity and antitumor activity, in particular for continuous infusion schedules, but to a lesser extent for frequently used bolus injections. The use of intensive sampling schedules limits the application of pharmacokinetics to optimize individual dosing or to define the ideal combination with other drugs. We therefore reanalyzed a pharmacokinetic study in order to develop a limited sampling schedule. Patients received escalating doses of 5FU at 500, 600 and 720 mg/m2 as a bolus until toxicity developed. Blood samples were analysed until 24 hr after administration. The area under the concentration time curve from 0-90 min (AUC0-90) strongly correlated with dose and also with toxicity (p = 0.0009). The 5FU concentrations at 30 and 60 min were correlated to the AUC30-240 and to that of AUC0-90 (r2= 0.970). Use of limited sampling (30, 60, 90 min) in a patient given 353 mg/m2 5FU with severe toxicity at initial dosing at 500 mg/m2 revealed that the AUC0-90 at 353 mg/m2 was higher than the normal AUC0-90 for 500 mg/m2. This patient appeared to have an 8-fold lower activity of the 5FU degradation enzyme dihydropyrimidine dehydrogenase. Limited sampling will allow to define potential aberrant kinetics of pharmacokinetic interaction of 5FU with other drugs being developed for treatment of colorectal cancer.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.