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

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.

Comparison of a new enzymatic assay with a high-performance liquid chromatography/ ultraviolet detection method for therapeutic drug monitoring of mycophenolic acid in adult liver transplant recipients.

Mycophenolic acid (MPA) is used to prevent graft rejection. The methods used for determining the plasma MPA concentration in liver transplant recipients are the enzyme-multiplied immunoassay technique (EMIT), high-performance liquid chromatography with ultraviolet detection (HPLC-UV), and most recently mass spectrometry. EMIT has been reported to overestimate the MPA concentration by 30% to 35% in comparison with HPLC-UV. Recently, a new automated enzymatic assay based on inosine monophosphate dehydrogenase inhibition has been designed. The aim of the present investigation was to compare this technique with validated HPLC-UV in adult liver transplant recipients treated with tacrolimus or cyclosporine. One hundred seventy-six samples from 50 adult liver transplant recipients were analyzed with both techniques. Patients received mycophenolate mofetil (2 or 3 times daily) coadministered with cyclosporine microemulsion (n = 18) or tacrolimus (n = 32). Samples were drawn over an interdose interval during the early or late posttransplantation period. The Passing-Bablok regression and Bland-Altman plot were used to compare the 2 techniques. The Passing-Bablock regression, calculated from 166 samples, showed very good agreement between the enzymatic assay and the HPLC-UV method: enzymatic assay = 1.0204 (95% confidence interval, 0.9942, 1.0478) x HPLC-UV + 0.0201 (-0.0442, 0.0882). No significant bias was found between the techniques (Bland-Altman plot), and the median relative difference was 2.7% (95% confidence interval, -0.4, 6.6). In conclusion, the enzymatic assay showed an excellent correlation with HPLC-UV. Therefore, this method was proved valid and reliable for the monitoring of the plasma MPA concentration in adult liver transplant recipients treated with cyclosporine microemulsion or tacrolimus.

Variability in free mycophenolic acid exposure in adult liver transplant recipients during the early posttransplantation period.

Mycophenolate mofetil (MMF) pharmacokinetics variability in liver transplant recipients during the early posttransplantation period may be related to changes in mycophenolic acid (MPA) protein binding. This study aimed at characterizing the variation of free MPA exposure with respect to time since transplantation. Three groups (A, B, C) were compared. The median posttransplantation time was 12 days (A, n = 26 pharmacokinetic sessions), 36 days (B, n = 25), and 867 days (C, n = 21). The median MPA AUC(0-12) in group A (26.8 mg x h/L) was significantly lower than in groups B (45.2 mg x h/L, P = .031) and C (43.5 mg x h/L, P = .004). Free MPA AUC(0-12) was comparable whatever the time (0.41, 0.34, and 0.33 mg x h/L, respectively). MPA apparent clearance (CL/F) was significantly correlated with MPA free fraction (r = 0.60, P < .0001) and approximately 1.7-fold higher in group A compared to groups B and C (P < .05). Enhanced CL/F in relation with an increase in MPA free fraction results in a low AUC of total MPA during the first postoperative month, but on average, at the population level, the exposure to free MPA is not altered, suggesting that total MPA AUC should not be used to adapt MMF dosing during this period.