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Saturable absorption of sorafenib in patients with solid tumors: a population model

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Summary

Sorafenib is an oral tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. By using a population approach, this study aimed to characterise its pharmacokinetics. Plasma concentration-time data (n = 372) from 71 patients under sorafenib were analysed using nonlinear mixed-effect modelling to estimate population pharmacokinetic parameters, as well as relationships between these parameters and different covariates (demographic, biological). Simulations were done to compare different daily dosing regimens in a context of dose-escalation. A 1-compartment model with saturated absorption, first-order intestinal loss and elimination best described the pharmacokinetics of sorafenib. Absolute bioavailability significantly dropped with increasing daily doses of sorafenib. AUC increased less than proportionally with increasing doses [47.3 (41.3–63.3), 60.3 (56.3–64.4), 71.4 (51.3–99.1), 75.9 (45.5–100.9) mg/L.h for 400, 800, 1,200 and 1,600 mg/day, respectively]. According to the simulations, dividing the daily dose in three or four doses for daily dose >800 mg would significantly increase AUC compared with a twice daily dosing regimen (101.7 vs 81.6 mg/L.h for 400 mg q8h and 600 mg q12h respectively; 131.6 vs 91.5 mg/L.h for 400 mg q6h and 800 mg q12h, respectively). Thrice daily regimen may be most suitable in a context of dose-escalation (>800 mg/day) in non-responders to standard-dosing regimen.

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Grant

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Conflicts of interest

F Goldwasser and S Ropert have acted as paid consultants for Bayer Healthcare. O Mir has acted as paid consultant for Roche. Other authors have no conflict of interest to declare.

Author information

Authors and Affiliations

  1. Laboratoire de pharmacologie-toxicologie, Service de Pharmacie, Hôpital Cochin, 75014, Paris, France

    Marilyne Hornecker, Benoit Blanchet, Hind Sassi, Fabrice Taieb, Halim Abbas, Laura Harcouet & Alain Dauphin

  2. Centre évaluation et de recours des inhibiteurs de l’angiogénèse (CERIA), Paris, France

    Benoit Blanchet, Bertrand Billemont, Stanislas Ropert, Olivier Mir, Romain Coriat & François Goldwasser

  3. Service d’oncologie, Hôpital Cochin, Paris, France

    Bertrand Billemont, Stanislas Ropert, Olivier Mir, Romain Coriat & François Goldwasser

  4. EA 1833 faculté de médecine Paris Descartes, Paris, Faculté de Médecine Paris 5, Paris, France

    Olivier Mir, Romain Coriat & François Goldwasser

  5. Pharmacie, Hôpital de la Croix-Rousse, Hospices civils de Lyon, Lyon, France

    Michel Tod

  6. Université de Lyon, 69008, Lyon, France

    Michel Tod

Authors
  1. Marilyne Hornecker
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  2. Benoit Blanchet
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  3. Bertrand Billemont
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  4. Hind Sassi
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  7. Olivier Mir
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  8. Halim Abbas
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  9. Laura Harcouet
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  10. Romain Coriat
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  11. Alain Dauphin
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  12. François Goldwasser
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  13. Michel Tod
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Corresponding author

Correspondence to Benoit Blanchet.

Additional information

Marilyne Hornecker and Benoit Blanchet contributed equally.

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Hornecker, M., Blanchet, B., Billemont, B. et al. Saturable absorption of sorafenib in patients with solid tumors: a population model. Invest New Drugs 30, 1991–2000 (2012). https://doi.org/10.1007/s10637-011-9760-z

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  • DOI: https://doi.org/10.1007/s10637-011-9760-z

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