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

  • Esther Oyaga-IriarteEmail author
  • Asier Insausti
  • Onintza Sayar
  • Azucena Aldaz
Pharmacokinetics and Disposition



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.


Irinotecan Population pharmacokinetic model Enterohepatic recirculation Parametric method Non-parametric method 


Authors’ contributions

AA conceived the study and contributed towards study design. EOI and AI analyzed the data. All authors were involved in the interpretation of data. EOI drafted the manuscript. OS and AA were involved in critical revision of the manuscript, with all study authors approving the final version for submission.


This work is partially supported by the “Ayuda para Doctorados Industriales del Ministerio de Economía, Industria y Competitividad” (Ref. DI-15-07511).

Compliance with ethical standards

This observational study was approved by the University Clinic of Navarre.

Conflict of interest

The authors declare that they have no conflicts of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Pharmamodelling S.L.PamplonaSpain
  2. 2.Department of Hospital PharmacyClínica Universidad de NavarraPamplonaSpain

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