title: Saturable absorption of sorafenib in patients with solid tumors: a population model.
abstract: 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.
authors: Laboratoire de pharmacologie-toxicologie, Service de Pharmacie, Hôpital Cochin, 75014, Paris, France.
authors: Marilyne
authors: M
authors: Hornecker
authors: Benoit
authors: B
authors: Blanchet
authors: Bertrand
authors: B
authors: Billemont
authors: Hind
authors: H
authors: Sassi
authors: Stanislas
authors: S
authors: Ropert
authors: Fabrice
authors: F
authors: Taieb
authors: Olivier
authors: O
authors: Mir
authors: Halim
authors: H
authors: Abbas
authors: Laura
authors: L
authors: Harcouet
authors: Romain
authors: R
authors: Coriat
authors: Alain
authors: A
authors: Dauphin
authors: François
authors: F
authors: Goldwasser
authors: Michel
authors: M
authors: Tod
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000077157:Sorafenib; D055815:Young Adult
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib