BACKGROUND: The relationship between 5-fluorouracil (5-FU) pharmacokinetics and toxicity following i.v. bolus administration has not been extensively studied. PATIENTS AND METHODS: One hundred and eighty-one patients on adjuvant therapy with 5-FU plus leucovorin for colorectal cancer were the study population. 5-FU pharmacokinetics was determined on day 2 of the first, third, and fifth cycles; type and the grade of adverse reactions were recorded on the next cycle. RESULTS: The 5-FU area under the curve (AUC) measured at the first cycle ranged between 146 and 1236 mg x min/l and was significantly correlated with drug dose, patients' body weight (BW) and gender, females having higher AUCs. These covariates explained only 23% of AUC variability. AUC and age were the only covariates which discriminated between toxic (grade > or =2) and nontoxic cycles (grade <2), with an optimal AUC cut-off value of 596 mg x min/l. Such a correlation was lost during the next cycles following dose reduction because of toxicity in 80 patients. CONCLUSIONS: A method for calculating the initial 5-FU dose is proposed which takes into account patient BW, gender and a target AUC of 596 mg x min/l. Nevertheless, it appears that a substantial part of 5-FU toxicity is not linked to pharmacokinetic factors and dose adjustments must still be on the basis of careful clinical surveillance.
BACKGROUND: The relationship between 5-fluorouracil (5-FU) pharmacokinetics and toxicity following i.v. bolus administration has not been extensively studied. PATIENTS AND METHODS: One hundred and eighty-one patients on adjuvant therapy with 5-FU plus leucovorin for colorectal cancer were the study population. 5-FU pharmacokinetics was determined on day 2 of the first, third, and fifth cycles; type and the grade of adverse reactions were recorded on the next cycle. RESULTS: The 5-FU area under the curve (AUC) measured at the first cycle ranged between 146 and 1236 mg x min/l and was significantly correlated with drug dose, patients' body weight (BW) and gender, females having higher AUCs. These covariates explained only 23% of AUC variability. AUC and age were the only covariates which discriminated between toxic (grade > or =2) and nontoxic cycles (grade <2), with an optimal AUC cut-off value of 596 mg x min/l. Such a correlation was lost during the next cycles following dose reduction because of toxicity in 80 patients. CONCLUSIONS: A method for calculating the initial 5-FU dose is proposed which takes into account patient BW, gender and a target AUC of 596 mg x min/l. Nevertheless, it appears that a substantial part of 5-FUtoxicity is not linked to pharmacokinetic factors and dose adjustments must still be on the basis of careful clinical surveillance.
Authors: Jan H Beumer; Edward Chu; Carmen Allegra; Yusuke Tanigawara; Gerard Milano; Robert Diasio; Tae Won Kim; Ron H Mathijssen; Li Zhang; Dirk Arnold; Katsuki Muneoka; Narikazu Boku; Markus Joerger Journal: Clin Pharmacol Ther Date: 2018-09-11 Impact factor: 6.875
Authors: André B P van Kuilenburg; Peter Häusler; Andreas Schalhorn; Michael W T Tanck; Johannes H Proost; Christoph Terborg; Detlev Behnke; Wolfgang Schwabe; Kati Jabschinsky; Jan Gerard Maring Journal: Clin Pharmacokinet Date: 2012-03-01 Impact factor: 6.447
Authors: K-p Kim; G Jang; Y S Hong; H-S Lim; K-s Bae; H-S Kim; S S Lee; J-G Shin; J-L Lee; M-H Ryu; H-M Chang; Y-K Kang; T W Kim Journal: Br J Cancer Date: 2011-02-15 Impact factor: 7.640
Authors: Barbara Schuster; Markus Hecht; Manfred Schmidt; Marlen Haderlein; Tina Jost; Maike Büttner-Herold; Klaus Weber; Axel Denz; Robert Grützmann; Arndt Hartmann; Hans Geinitz; Rainer Fietkau; Luitpold V Distel Journal: Cancers (Basel) Date: 2021-12-29 Impact factor: 6.639
Authors: M Gusella; A C Frigo; C Bolzonella; R Marinelli; C Barile; A Bononi; G Crepaldi; D Menon; L Stievano; S Toso; F Pasini; E Ferrazzi; R Padrini Journal: Br J Cancer Date: 2009-04-21 Impact factor: 7.640