Circadian rhythm of 5-fluorouracil population pharmacokinetics in patientswith metastatic colorectal cancer

Purpose: The purpose of this work was to estimate the population pharmacoki netic parameters of 5-fluorouracil (5-FU) in patients with advanced colorec tal cancer using circadian change kinetics. Methods: Eighty-five patients ( 32 females, 53 males) were enrolled onto this study. All patients received folinic acid (200 mg/m(2)) by intravenous infusion over 2 h followed by a 5 -FU loading dose (400 mg/m(2)) and then continuous infusion (600 mg/m(2)) f or 22 h. This whole regimen was repeated on day 2 and was given on a 14-day cycle. Plasma 5-FU determinations were performed by high-performance liqui d chromatography with ultraviolet absorbance detection. Pharmacokinetic ana lyses were performed using the NONMEM computer program through the Visual-N M graphical interface. An open one-compartment pharmacokinetic model with z ero-order input rate was used to describe the kinetics of 5-FU; moreover, c ircadian time-dependent changes in 5-FU concentrations were taken into acco unt in the model. The circadian model was defined as the sum of two cyclic components; the amplitude of the first cyclic component (over 24 h) was abo ut 30% of the average clearance and the amplitude of the second cyclic comp onent (over 12 h) was about 50% of the amplitude of the first component. Th e acrophase (peak) times of the first and the second periodic component wer e 04 h 12 m and 00 h 25 m, respectively. The potential sources of variabili ty on the population parameters (65 patients) were investigated using patie nt's sex, body area, age, body weight; height, liver enzymes and serum crea tinine as covariables. Results: Only the estimated clearance circadian chan ges were different for the two sexes. The population parameter estimates of mean clearance (CLmean) and initial volume of distribution (V), were as fo llows: the male subgroup showed a CLmean value twice larger (125 l/h) than the value observed in the female subgroup (65 l/h), and V = 21 l. A validat ion group of 20 additional patients was used to evaluate the predictive per formances of the population parameters. The individual pharmacokinetic para meters were computed by means of a Bayesian fitting procedure. From the res ulting individualized parameter values, concentrations of 5-FU in the plasm a were calculated. To evaluate the performance of the Bayesian estimation, the experimental concentrations were compared with the predicted ones. Conc lusion: In conclusion, a chronomodulated delivery schedule of 5-FU should b e performed, using a perfusion rate inversely proportional to the circadian variations of clearance in order to maintain stable 5-FU plasma levels. Su ch a treatment schedule may result in increased effectiveness of the treatm ent and decreased occurrence of drug-associated side-effects. The present s tudy develops a complete procedure to efficiently estimate 5-FU clearance i n order to optimize dosage regimens in individual patients.