Population pharmacokinetic model of irinotecan and its metabolites in patients with metastatic colorectal cancer.

Irinotecan (CPT-11) is a drug used against a wide range of tumor types. The individualized dosing of CPT-11 is essential to ensure optimal pharmacotherapy in cancer patients, given the wide interindividual pharmacokinetic variability of this drug and its active metabolite SN-38. Moreover, the reabsorption from SN-38-G to SN-38, by enterohepatic recirculation, is critical due to its influence in the treatment tolerance. The aim of this research was to build a joint population pharmacokinetic model for CPT-11 and its metabolites (SN-38, and its glucuronide, SN-38-G) that enabled an individualized posology adjustment. We used data of 53 treatment cycles of FOLFIRINOX scheme corresponding to 20 patients with metastatic colorectal cancer. In order to build the population pharmacokinetic model, we implemented parametric and non-parametric methods using the Pmetrics library package for R. We also built multivariate regression models to predict the area under the curve and the maximum concentration using basal covariates. The final model was a multicompartmental model which represented the transformations from CPT-11 to its active metabolite SN-38 and from SN-38 to inactive SN-38-G. Besides, the model also represented the extensive elimination of SN-38-G and the reconversion of the remaining SN-38-G to SN-38 by enterohepatic recirculation. We carried out internal validation with 1000 simulations. The regression models predicted the PK parameters with R squared adjusted up to 0.9499. CPT-11, SN-38, and SN-38-G can be correctly described by the multicompartmental model presented in this work. As far as we know, it is the first time that a joint model for CPT-11, SN-38, and SN-38-G that includes the process of reconversion from SN-38-G to SN-38 is characterized.