R. Gieschke, B. Reigner, J.-L. Steimer
Pharma Development, F. Hoffmann - La Roche Basel, Switzerland.
XELODAä (capecitabine) is a novel fluoropyrimidine carbamate for oral treatment of solid tumors. It is extensively absorbed and metabolized in the liver to 5′-DFCR, followed by conversion to 5′-DFUR by cytidine deaminase, principally located in the liver and tumor tissues. The activation of 5′-DFUR to the chemotherapeutic agent 5-FU by thymidine phosphorylase occurs selectively in the tumor, as compared to adjacent healthy tissue. 5-FU is finally catabolized to FBAL which is excreted in the urine.
The objectives of the present analyses were (i) to develop a suitable pharmacokinetic (PK) model for describing the time course of plasma concentrations of 5′-DFUR, 5-FU and FBAL following oral administration of capecitabine, and (ii) to evaluate the influence of covariates (i.e. gender, age, body surface area (BSA), cancer type, creatinine clearance, total bilirubin, and liver metastasis assessed at baseline) on the pharmacokinetics of the capecitabine metabolites. Using the software NONMEM, a linear multiresponse population PK model was developed based on data from a bioequivalence study (n=24) where extensive blood sampling was performed. A catenary three compartment model (one compartment per metabolite) revealed adequate in the investigated dose range. The “L2 data item” as available in NONMEM allowed to properly account for correlated errors in the metabolites measurements. Predictive performance of the model was assessed using model predicted vs. non-compartmentally determined AUC values.
Sparsely sampled data were obtained on the first day of treatment cycles 2, 3 and 4 (each cycle being two weeks of treatment at 2510 mg/sqm/day followed by one week rest) from Phase II breast cancer patients (n=54). After addition of the sparse data into the NONMEM analysis, the model was used to evaluate the influence of above covariates on the following main PK parameters: apparent oral clearances of 5′-DFUR, 5-FU and FBAL and apparent volume of distribution of FBAL. SUnconfounded (remove Unconfounded, or make a point on confounding elsewhere) tatistically significant effects were detected for gender, BSA and total bilirubin (on 5′-DFUR clearance) and for creatinine clearance (on FBAL clearance). Major effects were shown for BSA (10% increase in BSA leads to a 12% increase in 5?-DFUR clearance) and creatinine clearance (50% decrease in creatinine clearance leads to a 30% decrease in FBAL clearance). However, none of these effects were of clinical relevance, i.e. there were no implications on the dosage regimen of capecitabine.
In conclusion, a population pharmacokinetic analysis revealed adequate for describing the pharmacokinetics of capecitabine metabolites 5′-DFUR, 5-FU and FBAL and the influence of covariates on exposure.
Reference: PAGE 8 (1999) Abstr 152 [www.page-meeting.org/?abstract=152]
Poster: poster