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

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Abstract

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.

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Abbreviations

AIC :

Akaike’s information criteria

BIC :

Bayesian information criteria

BSV :

Between-subject variability

COSSAC :

Conditional sampling use for stepwise approach on correlation tests

IWRES :

Individual weighted residuals

ED-optimality :

D-optimality with expected distribution

FOLFIRI :

Combination of irinotecan (CPT-11) and 5-fluorouracil/leucovorin

HPLC :

High-performance liquid chromatography

IPRED :

Individual predicted

IV :

Intravenous

LLOQ :

Lower limit of quantitation

LRT :

Likelihood ratio test

LV :

Leucovorin

MCMC :

Markov chain Monte Carlo

pcVPC :

Prediction-corrected visual predictive check

PPRED :

Population predicted

SAEM :

Stochastic approximation of the standard expectation maximization

5-FU :

5-fluorouracil

%ME :

Percent mean error

%MAE :

Percent mean absolute error

%RMSE :

Percent root mean squared error

%RSE :

Percent relative standard error

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Acknowledgments

The authors would like to thank Dr. Pauline Traynard at Lixoft for her expert advice on Monolix and the Information Technology Services Research Computing group at University of North Carolina at Chapel Hill for their technical support.

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Authors and Affiliations

  1. Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Spinel Karas, Amy S. Etheridge, Eleftheria Tsakalozou, Alan Forrest & Federico Innocenti

  2. Department of Medicine, University of Chicago, Chicago, IL, USA

    Jacqueline Ramírez & Mark J. Ratain

  3. Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy

    Erika Cecchin & Giuseppe Toffoli

  4. Department of Clinical Chemistry, Erasmus MC, Rotterdam, Netherlands

    Ron H.N. van Schaik

  5. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands

    Ron H.J. Mathijssen

  6. Department of Pharmaceutical Sciences, University at Buffalo School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA

    Robert R. Bies

  7. Computational and Data Enabled Sciences and Engineering Program, University at Buffalo, State University of New York at Buffalo, Buffalo, NY, USA

    Robert R. Bies

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  1. Spinel Karas
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Correspondence to Robert R. Bies or Federico Innocenti.

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Karas, S., Etheridge, A.S., Tsakalozou, E. et al. Optimal Sampling Strategies for Irinotecan (CPT-11) and its Active Metabolite (SN-38) in Cancer Patients. AAPS J 22, 59 (2020). https://doi.org/10.1208/s12248-020-0429-4

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