Optimal Sampling Strategies for Irinotecan (CPT-11) and its Active Metabolite (SN-38) in Cancer Patients

Spinel Karas, Amy S. Etheridge, Eleftheria Tsakalozou, Jacqueline Ramírez, Erika Cecchin, Ron H.N. van Schaik, Giuseppe Toffoli, Mark J. Ratain, Ron H.J. Mathijssen, Alan Forrest, Robert R. Bies, Federico Innocenti

Research output: Contribution to journalArticlepeer-review


Irinotecan (CPT-11) is an anticancer agent widely used in the treatment of a variety of adult solid tumors. The objective of this study was to develop an optimal sampling strategy model that accurately estimates pharmacokinetic parameters of CPT-11 and its active metabolite, SN-38. This study included 221 patients with advanced solid tumors or lymphoma receiving CPT-11 single or combination therapy with 5-fluorouracil (5-FU)/leucovorin (LV) (FOLFIRI) plus bevacizumab from 4 separate clinical trials. Population pharmacokinetic analysis of CPT-11 and SN-38 was performed by non-linear mixed effects modeling. The optimal sampling strategy model was developed using D-optimality with expected distribution approach. The pharmacokinetic profiles of CPT-11 and SN-38 were best described by a 3- and 2-compartment model, respectively, with first-order elimination. Body surface area and co-administration with 5-FU/LV plus bevacizumab were significant covariates (p < 0.01) for volumes of the central compartment of CPT-11 and SN-38, and clearance of CPT-11. Pre-treatment total bilirubin and co-administration with 5-FU/LV and bevacizumab were significant covariates (p < 0.01) for clearance of SN-38. Accurate and precise predictive performance (r2 > 0.99, -2 < bias (%ME) < 0, precision (% RMSE) < 12) of both CPT-11 and SN-38 was achieved using: (i) 6 fixed sampling times collected at 1.5, 3.5, 4, 5.75, 22, 23.5 hours post-infusion; or (ii) 1 fixed time and 2 sampling windows collected at 1.5, [3-5.75], [22-23.5] hours post-infusion. The present study demonstrates that an optimal sampling design with three blood samples achieves accurate and precise pharmacokinetic parameter estimates for both CPT-11 and SN-38.

Original languageEnglish
Article number59
Number of pages15
JournalAAPS Journal
Issue number3
Publication statusPublished - May 1 2020


  • irinotecan (CPT-11)
  • limited sampling
  • optimal sampling strategy
  • population pharmacokinetics
  • SN-38

ASJC Scopus subject areas

  • Pharmaceutical Science


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