Gender-specific elimination of continuous-infusional 5-fluorouracil in patients with gastrointestinal malignancies: results from a prospective population pharmacokinetic study

• Published in: Cancer chemotherapy and pharmacology 2013-02, Vol.71 (2), p.361-370
• Main Authors: Mueller, F., Büchel, B., Köberle, D., Schürch, S., Pfister, B., Krähenbühl, St, Froehlich, T. K., Largiader, C. R., Joerger, M.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic - pharmacokinetics; Antineoplastic agents; Biological and medical sciences; Cancer Research; Dihydrouracil Dehydrogenase (NADP) - metabolism; Female; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Fluorouracil - pharmacokinetics; Gastroenterology. Liver. Pancreas. Abdomen; Gastrointestinal Neoplasms - drug therapy; Gastrointestinal Neoplasms - metabolism; Humans; Infusions, Intravenous; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Prospective Studies; Sex Characteristics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-012-2018-4

Background This study was initiated to assess the quantitative impact of patient anthropometrics and dihydropyrimidine dehydrogenase ( DPYD ) mutations on the pharmacokinetics (PK) of 5-fluorouracil (5FU) and to explore limited sampling strategies of 5FU. Patients and methods We included 32 patients with gastrointestinal malignancies, receiving 46-h continuous-infusional 5FU and performed PK-sampling at baseline, 15, 30, 45 min, 1 and 2 h after the start of infusion and at the end of infusion, for 2 subsequent cycles. Plasma concentrations of 5FU, 5-fluorodihydrouracil (5FUH2), uracil (U) and 5,6-dihydrouracil (UH2) were determined using LC–MS/MS and submitted to population PK analysis using nonlinear mixed-effects modeling. Broad genotyping of DPYD was performed, and the potential impact of the DPYD genotype on the elimination of 5FU was assessed. Limited sampling strategies were evaluated for their accuracy to predict steady-state concentrations of 5FU (CSS 5FU ), using data simulations based on the final PK-model. Results The area-under-the concentration–time curve of 5FU (AUC 5FU ) was found to be 30 mg h/L in 7 occasions (12 %). Men had a 26 % higher elimination of 5FU and a 18 % higher apparent elimination of 5FUH2. Accordingly, women had a higher AUC 5FU compared to men (22 vs. 18 mg h/L, p  = 0.04). No DPYD risk variants were found, and the DPYD variants detected (c.496A>G, c.1601G>A, c.1627A>G) were not significantly associated with the elimination of 5FU. Individual baseline UH 2 /U ratio was significantly associated with AUC 5FU ( R  = −0.49, p