Optimal Sampling Strategies for Irinotecan (CPT-11) and its Active Metabolite (SN-38) in Cancer Patients
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.
|Keywords||irinotecan (CPT-11), limited sampling, optimal sampling strategy, population pharmacokinetics, SN-38|
|Persistent URL||dx.doi.org/10.1208/s12248-020-0429-4, hdl.handle.net/1765/125787|
Karas, S. (Spinel), Etheridge, A.S. (Amy S.), Tsakalozou, E. (Eleftheria), Ramirez, J, Cecchin, E. (Erika), van Schaik, R.H.N, … Innocenti, F. (2020). Optimal Sampling Strategies for Irinotecan (CPT-11) and its Active Metabolite (SN-38) in Cancer Patients. AAPS Journal, 22(3). doi:10.1208/s12248-020-0429-4