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A pharmacokinetic‐based test to prevent severe 5‐fluorouracil toxicity
Author(s) -
Bocci Guido,
Barbara Cecilia,
Vannozzi Francesca,
Di Paolo Antonello,
Melosi Alessandro,
Barsanti Gemma,
Allegrini Giacomo,
Falcone Alfredo,
Del Tacca Mario,
Danesi Romano
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2006.06.007
Subject(s) - pharmacokinetics , dihydropyrimidine dehydrogenase , folinic acid , fluorouracil , medicine , pharmacology , toxicity , antimetabolite , chemotherapy , gastroenterology , thymidylate synthase
Background and Objectives Dihydropyrimidine dehydrogenase (DPD) plays a key role in the catabolism of 5‐fluorouracil (5‐FU) to 5‐fluoro‐5,6‐dihydrouracil (5‐FDHU), and as such, an impairment of DPD has been recognized as an important factor for altered 5‐FU and 5‐FDHU pharmacokinetics, predisposing patients to the development of severe 5‐FU‐associated toxicity. Our objectives were to avoid severe 5‐FU toxicities in patients with greatly impaired 5‐FU and 5‐FDHU pharmacokinetics after the administration of a reduced test dose of 5‐FU and to investigate possible 5‐FU or 5‐FDHU pharmacokinetic parameters of the test dose related to the most common drug toxicities that affect patients after the first cycle of 5‐FU chemotherapy. Methods Pharmacokinetics of 5‐FU/5‐FDHU and DPD activity in peripheral blood mononuclear cells (PBMCs) were examined in 188 gastrointestinal cancer patients given a test dose of 5‐FU, 250 mg/m 2 , 2 weeks before starting the planned 5‐FU treatment of 370 mg/m 2 plus L ‐folinic acid, 100 mg/m 2 , for 5 days every 4 weeks. Drug levels were examined by HPLC, and toxicities were graded according to World Health Organization criteria. Results The 5‐FU test dose was well tolerated in all patients. Of 188 patients, 3 (1.6%) had marked alterations of 5‐FU/5‐FDHU pharmacokinetics (ie, 5‐FU half‐life [t ½β ] >5 hours, 5‐FU total body clearance [CL TB ] <1 L · h −1 · m −2 , and 5‐FDHU time to reach maximum plasma concentration [t max ] ≥45 minutes); they were excluded from 5‐FU treatments and treated with irinotecan, which was well tolerated. The plasma disposition of 5‐FU in the remaining 185 patients revealed an area under the curve (AUC) of 3.73 ± 2.18 h · μg/mL (mean ± SD), maximum plasma concentration (C max ) of 16.78 ± 8.61 μg/mL, and t ½β of 0.16 ± 0.15 hour, whereas the CL TB was 65.67 ± 31.86 L · h −1 · m −2 . The 5‐FDHU plasma profile showed a C max value of 3.64 ± 1.94 μg/mL, whereas the t max value was 26.63 ± 10.06 minutes, with an AUC value of 3.71 ± 1.90 h · μg/mL. The PBMC DPD activity was 202.15 ± 141.14 pmol 5‐FDHU · min −1 · mg −1 protein (95% confidence interval, 165–239.3 pmol 5‐FDHU · min −1 · mg −1 protein). A significant correlation between 5‐FU AUC and 5‐FDHU AUC was found ( r = 0.5492, P < .0001), whereas a weaker correlation between PBMC DPD activity and both 5‐FDHU AUC ( r = 0.328, P = .0121) and 5‐FDHU C max ( r = 0.369, P = .0044) was found. Interestingly, no relationships between PBMC DPD activity and common toxicities were found, whereas 5‐FDHU t max values greater than 30 minutes were associated with the risk of moderate to severe neutropenia and diarrhea ( P = .0323 and P = .0138, respectively; chi‐square test). Conclusions This study suggests a successful approach for preventing severe or life‐threatening toxicities in gastrointestinal cancer patients who are candidates for standard 5‐FU treatment by analyzing the 5‐FU and 5‐FDHU pharmacokinetic parameters after the administration of a reduced 5‐FU test dose. Clinical Pharmacology & Therapeutics (2006) 80 , 384–395; doi: 10.1016/j.clpt.2006.06.007