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.
Subject(s)
Neoplasms/drug therapy , Neoplasms/metabolism , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/pharmacokinetics , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Absorption , Administration, Oral , Adult , Aged , Aged, 80 and over , Biological Availability , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Models, Biological , Niacinamide/administration & dosage , Niacinamide/pharmacokinetics , Sorafenib , Young AdultABSTRACT
Mycophenolic acid (MPA) is 98-99% bound to albumin. Because MPA is restrictively cleared and has a low extraction coefficient, increase in its free fraction related to decreased albumin binding results in lower total concentrations but unchanged unbound concentrations. Multiple factors, including hypoalbuminemia, impaired renal function, and accumulated mycophenolic acid glucuronide are known to reduce MPA protein binding. Little is known about the influence of fatty acids and bilirubin on this issue. By using quenching fluorescence method, the aims of this study were to investigate in vitro the binding properties of MPA, then the influence of myristic acid and bilirubin on MPA binding to albumin. The estimate of dissociation constant (Kd) of MPA was 13.2 [CI 95 12.7-13.8] µM. In the presence of myristic acid (concentration range 4-100 µM), apparent Kd (Kd(app)) of MPA was approximately 1.5-10-fold greater. For myristic acid/albumin molar ratio reachable in clinical settings (2:1 and 5:1), Kd(app) of MPA rose about a factor 1.5 and 2.2, respectively. In the presence of bilirubin (concentration range 0.5-5 µM), Kd(app) of MPA was approximately 1.5-5-fold greater than MPA Kd. For bilirubin/albumin molar ratio reachable in clinical settings (1:4 and 1:2), Kd(app) of MPA rose about a factor 1.5 and 1.9, respectively. These data suggest that hypertriglyceridemia or cholestasis may significantly increase MPA free fraction in clinical settings, thereby lowering MPA total concentration in plasma while the free concentration remains unchanged. These results may help to optimize the therapeutic drug monitoring of MPA.
