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.

Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen.

BACKGROUND: Hydroxyurea (HU) is the first approved pharmacological treatment of sickle cell anemia (SCA). The objectives of this study were to develop population pharmacokinetic(PK)-pharmacodynamic(PD) models for HU in order to characterize the exposure-efficacy relationships and their variability, compare two dosing regimens by simulations and develop some recommendations for monitoring the treatment. METHODS: The models were built using population modelling software NONMEM VII based on data from two clinical studies of SCA adult patients receiving 500-2000 mg of HU once daily. Fetal hemoglobin percentage (HbF%) and mean corpuscular volume (MCV) were used as biomarkers for response. A sequential modelling approach was applied. Models were evaluated using simulation-based techniques. Comparisons of two dosing regimens were performed by simulating 10000 patients in each arm during 12 months. RESULTS: The PK profiles were described by a bicompartmental model. The median (and interindividual coefficient of variation (CV)) of clearance was 11.6 L/h (30%), the central volume was 45.3 L (35%). PK steady-state was reached in about 35 days. For a given dosing regimen, HU exposure varied approximately fivefold among patients. The dynamics of HbF% and MCV were described by turnover models with inhibition of elimination of response. In the studied range of drug exposures, the effect of HU on HbF% was at its maximum (median Imax was 0.57, CV was 27%); the effect on MCV was close to its maximum, with median value of 0.14 and CV of 49%. Simulations showed that 95% of the steady-state levels of HbF% and MCV need 26 months and 3 months to be reached, respectively. The CV of the steady-state value of HbF% was about 7 times larger than that of MCV. Simulations with two different dosing regimens showed that continuous dosing led to a stronger HbF% increase in some patients. CONCLUSIONS: The high variability of response to HU was related in part to pharmacokinetics and to pharmacodynamics. The steady-state value of MCV at month 3 is not predictive of the HbF% value at month 26. Hence, HbF% level may be a better biomarker for monitoring HU treatment. Continuous dosing might be more advantageous in terms of HbF% for patients who have a strong response to HU. TRIAL REGISTRATION: The clinical studies whose data are analysed and reported in this work were not required to be registered in France at their time. Both studies were approved by local ethics committees (of Mondor Hospital and of Kremlin-Bicetre Hospital) and written informed consent was obtained from each patient.

No effect of CYP450 and P-glycoprotein on hydroxyurea in vitro metabolism.

Our objectives were (1) to study the HU metabolism via human cytochromes and (2) to test if HU is a substrate of P-gp. HU metabolism was investigated by determining the appearance of urea and HU decreasing upon incubation with human liver microsomes. Quantification was determined using HPLC coupled with UV-detection at 449 nm. Our method was linear between 5 and 1000 microm, precise (coefficients of variation ranging from 1.7 to 9.9%), accurate (97.7-103.9%). The limit of quantification was 7 microm. The ATPase activity of human P-gp membranes was determined by measuring inorganic phosphate liberation. HU and urea measurements in microsomes were not different between 0 and 60 min whatever HU concentration used from 30 to 300 microm. The presence of NADPH in the medium has no effect on HU and urea measurements. In the absence of verapamil, the ATPase activity was unaffected by HU at concentrations of 10, 30, 100 and 300 microm. HU is unlikely to cause clinically relevant drug interactions with the substrates of these enzymes/transporters. However, it will be necessary to validate these in vitro data in patients with sickle cell anemia to evaluate the impact of genetic polymorphisms of these enzymes in a black population.