Pharmacokinetic modelling of 5-FU production from capecitabine--a population study in 40 adult patients with metastatic cancer.
OBJECTIVE
To model the biotransformation steps of 5-FU production from capecitabine and identify patient characteristics that may influence the drug disposition.


METHODS
Blood samples and demographic data were collected from two phase I studies in which adult patients received oral capecitabine for various malignancies. Capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR) and 5-fluorouracile (5-FU) concentration-time data were analysed via a population approach using NONMEM.


RESULTS
Forty patients and 75 pharmacokinetic time-courses were available for analysis. Capecitabine pharmacokinetics was ascribed to a one compartment model from which 5'-DFCR, 5'-DFUR and 5-FU were sequentially produced. Capecitabine oral absorption was characterized by a rapid first order input (K(a)=2.1 +/- 0.3 hr(-1)) with a lag time (0.28 +/- 0.11 hr), but related inter-occasion (IOV) and inter-subject (ISV) variabilities for these parameters, 167% and 110%, indicated that this oral absorption was highly variable. The capecitabine CL (CL10 = 218+/- 18 L/hr, ISV = 18%) and 5'-DFUR elimination rate constant (K34 = 5.3 +/- 2.0 hr(-1), ISV = 25%) were influenced by total bilirubin (BILT). The elimination rate constant of plasma 5-FU (K40) was 66 +/- 24 hr(-1) (ISV = 34%). The final pharmacokinetic model was validated using 2000 bootstrap runs and provided non-parametric statistics of the parameters (median, 2.5th and 97.5th percentiles).


CONCLUSIONS
This study supported the possibility of modelling a complex sequential metabolic pathway which produces pharmacologicaly active compounds from a prodrug. Only BILT significantly influenced the pharmacokinetics but this effect was not considered as relevant for dosing adjustment.
Urien
Saik
S
Pharmacology Department, Centre René Huguenin, Saint-Cloud, France. s.urien@stcloud-huguenin.org
Rezaí
Keyvan
K
Lokiec
François
F
D000328:Adult; D000368:Aged; D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069287:Capecitabine; D002851:Chromatography, High Pressure Liquid; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005467:Floxuridine / Q000097:blood; D005472:Fluorouracil / Q000097:blood*; D006801:Humans; D000077146:Irinotecan; D008875:Middle Aged; D008954:Models, Biological; D015394:Molecular Structure; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics; D012717:Sesquiterpenes / Q000008:administration & dosage
C509297:336 5'-FU; C509298:354 5'-DFCR; D011355:Prodrugs; D012717:Sesquiterpenes; D005467:Floxuridine; D003841:Deoxycytidine; D000069287:Capecitabine; C102714:irofulven; D000077146:Irinotecan; D005472:Fluorouracil; C025034:doxifluridine; D002166:Camptothecin