Population Pharmacokinetics of 5FU and its Major Metabolite 5-FDHU in Colorectal Cancer Patients
C. Woloch (1), J. Ciccolini (1), A. Di Paolo(2), A. Iliadis (1)
(1) Dpt. of Pharmacokinetics, UMR-MD3, University of Méditerrannée, Marseilles, France (2) Division of Pharmacology and Chemotherapy, Dpt. of Internal medicine, University of Pisa, Pisa, Italy
Objectives: Develop a population pharmacokinetic model for both 5-fluorouracile (5FU) and 5-fluoro-5,6-dihydrouracil (5-FDHU) to explore mechanisms and factors affecting 5-FU metabolism. The key enzyme implied in this metabolism is the dihydropyrimidine deshydrogenase (DPD). DPD is probably associated with severe toxicities in DPD-deficient patients [1].
Methods: Data came from a retrospective study on 129 colorectal cancer patients who received 6 cycles of 5-FU 370 mg/m2/day i.v. boluses (5 days every 4 weeks) and l-leucovorin 100 mg/m2/day, one month later after chirurgical resection. Demographic and biological data (gender, age, weight, liver enzyme, PBMC-DPD activity ...) were recorded from patient files and considered as covariates. Individual plasma concentrations of 5-FU and 5-FDHU were determined on day 1 of the first cycle with a validated high performance liquid chromatography method. A simultaneous model for the 5FU/5-FDHU concentration-time data system was performed using the population approach implemented in NONMEM VI.
Results: The pharmacokinetic of 5FU and 5-FDHU was well described by a three compartment model. Central and peripheral compartment were associated with 5FU and a single compartment was associated with 5-FDHU. Inter-individual variability was described by exponential terms and residual variability by a proportional error model. The elimination from the central compartment of 5FU was best described by a nonlinear Michaelis-Menten process and that of 5-FDHU, by a first order linear process.
Parameters describing the model:
- 5FU total clearance, CL,
- 5FU inter-compartmental clearance, Q,
- 5FU distribution volume of the central compartment, V1,
- 5FU distribution volume of the peripheral compartment, V2,
- 5FU metabolism rate, Vmax,
- 5FU Michaelis-Menten constant, Km,
- 5-FDHU volume of distribution, Vm,
- 5-FDHU clearance, CLm
Structural hypotheses:
- V2=3xV1,
- Vm=V1,
- interindividual variability of Q was fixed at 70% for which the objective function was the lower.
The table summarizes results of the population analysis.
Parameter | Typical Value (RSE %) | Interindividual variability (%) |
CL (L/h) | 33.6 (11.8) | 41.7 (11.3) |
Q (L/h) | 5.81 (7.8) | - |
V1 (L) | 21.6 (4.3) | 49.8 (15.8) |
Vmax (mg/h) | 396 (25.2) | 67.0 (20.1) |
Km (mg/L) | 24.5 (13.1) | 65.2 (27.8) |
CLm (L/h) | 15.6 (6.0) | 68.6 (10.8) |
Residual variability for the 5FU and 5-FDHU kinetic profiles was 14.7% (16.1%) and 19.7% (13.3%), respectively. The covariance matrix was obtained and post hoc estimates were obtained without shrinkage. Covariates included in the final model, were weight on V1, body surface area on CL and Vmax. No covariates were found to explain the interindividual variability of CLm.
Conclusions: This population PK model is the first one which integrates a nonlinear process describing the metabolism of 5FU to 5-FDHU. It could be used to assess relationships between exposures of both 5FU and 5-FDHU and related toxicities or efficacy.
Reference:
[1]. Di Paolo A, Danesi R, Falcone A, Cionini L, Vannozzi F, Masi G, Allegroni G, Mini E, Bocci G, Conte PF, Del Tacca M. Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients. Ann Oncol 2001;12(9):1301-6
