Population pharmacokinetics and concentration–effect relationships of capecitabine metabolites in colorectal cancer patients

Aims To assess the relationship between systemic exposure to capecitabine metabolites and parameters of efficacy and safety in patients with advanced or metastatic colorectal cancer from two phase III studies. Methods Concentration–effect analyses were based on data from 481 patients (248 males, 193 females; age range 27–86 years) in two phase III studies. Plasma concentration–time data for 5′‐deoxy‐5‐fluorouridine (5′‐DFUR), 5‐fluorouracil (5‐FU) and α‐fluoro‐β‐alanine (FBAL) were obtained from sparse blood samples collected within the time windows 0.5–1.5 h, 1.5–3.0 h, and 3.0–5.0 h after capecitabine administration (1250 mg m−2) on the first day of cycles 2 (day 22) and 4 (day 64), respectively. Systemic exposure based on plasma concentrations of capecitabine and its metabolites was determined using individual parameter estimates derived from a population pharmacokinetic model constructed for this purpose in NONMEM. Logistic regression analysis was conducted for selected safety parameters (all treatment‐related grade 3–4 adverse events, treatment‐related grade 3–4 diarrhoea, grade 3 hand–foot syndrome (HFS) and grade 3–4 hyperbilirubinaemia) and for tumour response. Cox regression analysis was used for the analysis of time‐to‐event data (time to disease progression and duration of survival). Results Statistically significant relationships between covariates and PK parameters were found as follows. A doubling of alkaline phosphatase activity was associated with a 11% decrease in 5‐FU clearance and a 12% increase in its AUC. A 50% decrease in creatinine clearance was associated with a 35% decrease in FBAL clearance, a 53% increase in its AUC, a 24% decrease in its volume of distribution, and a 41% increase in its Cmax. A 30% increase in body surface was associated with a 24% increase in the volume of distribution of FBAL and a 19% decrease in its Cmax. There was a broad overlap in systemic drug exposure between patients regardless of the occurrence of treatment‐related grade 3–4 adverse events or response to treatment, leading to weak relationships between systemic exposure to capecitabine metabolites and the safety and efficacy parameters. Of 42 concentration–effect relationships investigated, only five achieved statistical significance. Thus, we obtained a positive association between the AUC of FBAL and grade 3–4 diarrhoea (P = 0.035), a positive association between the AUC of 5‐FU and grade 3–4 hyperbilirubinaemia (P = 0.025), a negative associa