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A pharmacokinetic-based test to prevent severe 5-fluorouracil toxicity.
Bocci, Guido MD, PhD; Barbara, Cecilia MD; Vannozzi, Francesca MD; Di Paolo, Antonello MD, PhD; Melosi, Alessandro MD; Barsanti, Gemma MD; Allegrini, Giacomo MD; Falcone, Alfredo MD; Del Tacca, Mario MD, PharmD; Danesi, Romano MD, PhD
[Miscellaneous Article] Clinical Pharmacology & Therapeutics. 80(4):384-395, October 2006.

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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/m2, 2 weeks before starting the planned 5-FU treatment of 370 mg/m2 plus L-folinic acid, 100 mg/m2, 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 [t1/2[beta]] >5 hours, 5-FU total body clearance [CLTB] <1 L [middle dot] h-1 [middle dot] m-2, and 5-FDHU time to reach maximum plasma concentration [tmax] >=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 [middle dot] [mu]g/mL (mean /- SD), maximum plasma concentration (Cmax) of 16.78 /- 8.61 [mu]g/mL, and t1/2[beta] of 0.16 /- 0.15 hour, whereas the CLTB was 65.67 /- 31.86 L [middle dot] h-1 [middle dot] m-2. The 5-FDHU plasma profile showed a Cmax value of 3.64 /- 1.94 [mu]g/mL, whereas the tmax value was 26.63 /- 10.06 minutes, with an AUC value of 3.71 /- 1.90 h [middle dot] [mu]g/mL. The PBMC DPD activity was 202.15 /- 141.14 pmol 5-FDHU [middle dot] min-1 [middle dot] mg-1 protein (95% confidence interval, 165-239.3 pmol 5-FDHU [middle dot] min-1 [middle dot] 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 Cmax (r = 0.369, P = .0044) was found. Interestingly, no relationships between PBMC DPD activity and common toxicities were found, whereas 5-FDHU tmax 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.