Advertisement

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
  • 39 Downloads

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords

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

Notes

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.

Funding

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.

References

  1. 1.
    Quetglas EG, Armuzzi A, Wigge S, Fiorino G, Barnscheid L, Froelich M, Danese S (2015) Review article: the pharmacokinetics and pharmacodynamics of drugs used in inflammatory bowel disease treatment. Eur J Clin Pharmacol 71:773–799.  https://doi.org/10.1007/s00228-015-1862-7 CrossRefGoogle Scholar
  2. 2.
    Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécourarn Y, Adenis A, Raoul J-L, Gourgou-Bourgade S, de la Fochardiere C, Bennouna J, Bachet J-B, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817–1825CrossRefGoogle Scholar
  3. 3.
    Muranaka T, Kuwatani M, Komatsu Y, Sawada K, Nakatsumi H, Kawamoto Y, Yuki S, Kubota Y, Kubo K, Kawahata S, Kawakubo K, Kawakami H, Sakamoto N (2017) Comparison of efficacy and toxicity of FOLFIRINOX and gemcitabine with nab-paclitaxel in unresectable pancreatic cancer. J Gastrointest Oncol 8:566–571.  https://doi.org/10.21037/jgo.2017.02.02 CrossRefGoogle Scholar
  4. 4.
    Burris H, Fields S (1994) Topoisomerase I inhibitors. An overview of the camptothecin analogs. Hematol Oncol Clin North Am 8:333–355CrossRefGoogle Scholar
  5. 5.
    Peterson C (2011) Drug therapy of cancer. Eur J Clin Pharmacol 67:437–447.  https://doi.org/10.1007/s00228-011-1011-x CrossRefGoogle Scholar
  6. 6.
    Berg AK, Buckner JC, Galanis E, Jaeckle KA, Ames MM, Reid JM (2015) Quantification of the impact of enzyme-inducing antiepileptic drugs on irinotecan pharmacokinetics and SN-38 exposure. J Clin Pharmacol 55:1303–1312.  https://doi.org/10.1002/jcph.543 CrossRefGoogle Scholar
  7. 7.
    Poujol S, Bressolle F, Duffour J, Abderrahim AG, Astre C, Ychou M, Pinguet F (2006) Pharmacokinetics and pharmacodynamics of irinotecan and its metabolites from plasma and saliva data in patients with metastatic digestive cancer receiving Folfiri regimen. Cancer Chemother Pharmacol 58:292–305.  https://doi.org/10.1007/s00280-005-0166-5 CrossRefGoogle Scholar
  8. 8.
    Valenzuela Jiménez B, González Sales M, Escudero Ortiz V, Martínez Navarro E, Pérez Ruixo C, Rebollo Liceaga J, González Manzano R, Pérez Ruixo JJ (2013) Influencia de los polimorfismos genéticos en UGT1A1, UGT1A7 and UGT1A9 sobre la farmacocinética de irinotecan, SN-38 y SN-38G. Farm Hosp 37:111–127.  https://doi.org/10.7399/FH.2013.37.2.386 Google Scholar
  9. 9.
    Wakefield J, Racine-Poon A (1995) An application of Bayesian population pharmacokinetic/pharmacodynamic models to dose recommendation. Stat Med 14:971–986.  https://doi.org/10.1002/sim.4780140917 CrossRefGoogle Scholar
  10. 10.
    Asuphon O, Montakantikul P, Houngsaitong J, Kiratisin P, Sonthisombat P (2016) Optimizing intravenous fosfomycin dosing in combination with carbapenems for treatment of Pseudomonas aeruginosa infections in critically ill patients based on pharmacokinetic/pharmacodynamic (PK/PD) simulation. Int J Infect Dis 50:23–29.  https://doi.org/10.1016/j.ijid.2016.06.017 CrossRefGoogle Scholar
  11. 11.
    Oteo I, Lukas JC, Leal N, Suarez E, Valdivieso A, Gastaca M, Ortiz De Urbina J, Calvo R (2013) Tacrolimus pharmacokinetics in the early post-liver transplantation period and clinical applicability via Bayesian prediction. Eur J Clin Pharmacol 69:65–74.  https://doi.org/10.1007/s00228-012-1300-z CrossRefGoogle Scholar
  12. 12.
    Usman M, Frey OR, Hempel G (2017) Population pharmacokinetics of meropenem in elderly patients: dosing simulations based on renal function. Eur J Clin Pharmacol 73:333–342.  https://doi.org/10.1007/s00228-016-2172-4 CrossRefGoogle Scholar
  13. 13.
    Oken M, Creech R, Tormey D, Horton J, Davis T, McFadden E, Carbone P (1982) Toxicity and response criteria of the eastern cooperative oncology group. Am J Clin Oncol 5:649–656CrossRefGoogle Scholar
  14. 14.
    Castellanos Lácar MC (2003) Farmacocinética y farmacodinamia de irinotecan en pacientes con carcinoma colorrectal metastásico. Universidad de NavarraGoogle Scholar
  15. 15.
    Escoriaza J, Aldaz A, Castellanos C, Calvo E, Giráldez J (2000) Simple and rapid determination of irinotecan and its metabolite SN-38 in plasma by high-performance liquid-chromatography: application to clinical pharmacokinetic studies. J Chromatogr B 740:159–168CrossRefGoogle Scholar
  16. 16.
    Jelliffe R, Schumitzky A, Van Guilder M, Wang X, Leary R (2001) Population pharmacokinetic models: parametric and nonparametric approaches In: 14th IEEE Symposium on Computer-Based Medical Systems (CBMS), pp 407–412Google Scholar
  17. 17.
    Leary R, Jelliffe R, Schumitzky A, Van Guilder M (2001) An adaptive grid non-parametric approach to pharmacokinetic and dynamic (PK/PD) population models. In: IEEE Symposium on Computer-Based Medical Systems pp 389–394Google Scholar
  18. 18.
    Neely MN, van Guilder MG, Yamada WM, Schumitzky A, Jelliffe RW (2012) Accurate detection of outliers and subpopulations with Pmetrics, a non-parametric and parametric pharmacometric modeling and simulation package for R. Ther Drug Monit 34:467–476.  https://doi.org/10.1097/FTD.0b013e31825c4ba6 CrossRefGoogle Scholar
  19. 19.
    Chen S, Yueh M-F, Bigo C, Barbier O, Wang K, Karin M, Nguyen N, Tukey RH (2013) Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11). Proc Natl Acad Sci 110:19143–19148.  https://doi.org/10.1073/pnas.1319123110 CrossRefGoogle Scholar
  20. 20.
    Xie R, Mathijssen RHJ, Sparreboom A, Verweij J, Karlsson MO (2002) Clinical pharmacokinetics of irinotecan and its metabolites: a population analysis. J Clin Oncol 20:3293–3301.  https://doi.org/10.1200/JCO.2002.11.073 CrossRefGoogle Scholar
  21. 21.
    Klein CE, Gupta E, Reid JM, Atherton PJ, Sloan JA, Pitot HC, Ratain MJ, Kastrissios H (2002) Population pharmacokinetic model for irinotecan and two of its metabolites, SN-38 and SN-38 glucuronide. Clin Pharmacol Ther 72:638–647.  https://doi.org/10.1067/mcp.2002.129502 CrossRefGoogle Scholar
  22. 22.
    Rosner GL, Panetta JC, Innocenti F, Ratain MJ (2008) Pharmacogenetic pathway analysis of irinotecan. Clin Pharmacol Ther 84:393–402.  https://doi.org/10.1038/clpt.2008.63 CrossRefGoogle Scholar
  23. 23.
    Gupta E, Lestingi TM, Mick R, Ramirez J, Vokes EE, Ratain MJ (1994) Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res 54:3723–3725Google Scholar
  24. 24.
    Mathjissen RHJ, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G, Sparreboom A (2001) Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 7:2182–2194.  https://doi.org/10.1163/156856001300248353 Google Scholar
  25. 25.
    Kodawara T, Higashi T, Negoro Y, Kamitani Y, Igarashi T, Watanabe K, Tsukamoto H, Yano R, Masada M, Iwasaki H, Nakamura T (2016) The inhibitory effect of ciprofloxacin on the β-Glucuronidase-mediated deconjugation of the irinotecan metabolite SN-38-G. Basic Clin Pharmacol Toxicol 118:333–337.  https://doi.org/10.1111/bcpt.12511 CrossRefGoogle Scholar
  26. 26.
    Czejka M, Gruenberger B, Kiss A, Farkouh A, Schueller J (2010) Pharmacokinetics of irinotecan in combination with biweekly cetuximab in patients with advanced colorectal cancer. Anticancer Res 30:2355–2360Google Scholar
  27. 27.
    Satoh T, Yasui H, Muro K, Komatsu Y, Sameshima S, Yamaguchi K, Sugihara K (2013) Pharmacokinetic assessment of irinotecan, SN-38, and SN-38-glucuronide: a substudy of the FIRIS study. Anticancer Res 33:3845–3854Google Scholar
  28. 28.
    Innocenti F, Iyer L, Ratain MJ (2001) Pharmacogenetics of anticancer agents: lessons from amonafide and irinotecan. Drug Metab Dispos 29:596–600Google Scholar
  29. 29.
    Raymond E, Boige V, Faivre S, Sanderink GJ, Rixe O, Vernillet L, Jacques C, Gatineau M, Ducreux M, Armand JP (2002) Dosage adjustment and pharmacokinetic profile of irinotecan in cancer patients with hepatic dysfunction. J Clin Oncol 20:4303–4312.  https://doi.org/10.1200/JCO.2002.03.123 CrossRefGoogle Scholar
  30. 30.
    Rouits E, Charasson V, Pétain A, Boisdron-Celle M, Delord JP, Fonck M, Laurand A, Poirier AL, Morel A, Chatelut E, Robert J, Gamelin E (2008) Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients. Br J Cancer 99:1239–1245.  https://doi.org/10.1038/sj.bjc.6604673 CrossRefGoogle Scholar
  31. 31.
    Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343:905–914CrossRefGoogle Scholar
  32. 32.
    Saltz LB, Douillard J-Y, Pirotta N, Alakl M, Gruia G, Awad L, Elfring GL, Locker PK, Miller LL (2001) Irinotecan plus fluorouracil/Leucovorin for metastatic colorectal cancer: a new survival standard. Oncologist 6:81–91CrossRefGoogle Scholar
  33. 33.
    Woillard JB, Debord J, Monchaud C, Saint-Marcoux F, Marquet P (2017) Population pharmacokinetics and Bayesian estimators for refined dose adjustment of a new tacrolimus formulation in kidney and liver transplant patients. Clin Pharmacokinet 56:1491–1498.  https://doi.org/10.1007/s40262-017-0533-5 CrossRefGoogle Scholar
  34. 34.
    Flint RB, ter Heine R, Spaans E, Burger DM, de Klerk JCA, Allegaert K, Knibbe CAJ, Simons SHP (2018) Simulation-based suggestions to improve ibuprofen dosing for patent ductus arteriosus in preterm newborns. Eur J Clin Pharmacol 74:1585–1591.  https://doi.org/10.1007/s00228-018-2529-y CrossRefGoogle Scholar
  35. 35.
    Kweekel D, Guchelaar HJ, Gelderblom H (2008) Clinical and pharmacogenetic factors associated with irinotecan toxicity. Cancer Treat Rev 34:656–669.  https://doi.org/10.1016/j.ctrv.2008.05.002 CrossRefGoogle Scholar
  36. 36.
    Bozdogan H (1987) Model selection and Akaike’s Information Criterion (AIC): the general theory and its analytical extensions. Psychometrika 52:345–370.  https://doi.org/10.1007/BF02294361 CrossRefGoogle Scholar

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

Personalised recommendations