e of sorafenib is approximately 25 - 48 hours. Sorafenib is metabolised primarily in the liver and undergoes oxidative metabolism, mediated by CYP 3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib conjugates may be cleaved in the gastrointestinal tract by bacterial glucuronidase activity, allowing reabsorption of unconjugated active substance. Co-administration of neomycin has been shown to interfere with this process, decreasing the mean bioavailability of sorafenib by 54%.
Sorafenib accounts for approximately 70 - 85 % of the circulating analytes in plasma at steady state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib. This metabolite comprises approximately 9 - 16 % of circulating analytes at steady state.
Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96 % of the dose was recovered within 14 days, with 77 % of the dose excreted in faeces, and 19 % of the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51 % of the dose, was found in faeces but not in urine, indicating that biliary excretion of unchanged active substance might contribute to the elimination of sorafenib.
Pharmacokinetics in special populations
Analyses of demographic data suggest that there is no relationship between pharmacokinetics and age (up to 65 years), gender or body weight.
Paediatric population
No studies have been conducted to investigate the pharmacokinetics of sorafenib in paediatric patients.
Race
There are no clinically relevant differences in pharmacokinetics between Caucasian and Asian subjects.
Renal impairment
In four Phase I clinical trials, steady state exposure to sorafenib was similar in patients with mild or moderate renal impairment compared to the exposures in patients with normal renal function. In a clinical pharmacology study (single dose of 400 mg sorafenib), no relationship was observed between sorafenib exposure and renal function in subjects with normal renal function, mild, moderate or severe renal impairment. No data is available in patients requiring dialysis.
Hepatic impairment
In hepatocellular carcinoma (HCC) patients with Child-Pugh A or B (mild to moderate) hepatic impairment, exposure values were comparable and within the range observed in patients without hepatic impairment. The pharmacokinetics (PK) of sorafenib in Child-Pugh A and B non-HCC patients were similar to the PK in healthy volunteers. There are no data for patients with Child-Pugh C (severe) hepatic impairment. Sorafenib is mainly eliminated via the liver, and exposure might be increased in this patient population.
The preclinical safety profile of sorafenib was assessed in mice, rats, dogs and rabbits.
Repeat-dose toxicity studies revealed changes (degenerations and regenerations) in various organs at exposures below the anticipated clinical exposure (based on AUC comparisons).
After repeated dosing to young and growing dogs effects on bone and teeth were observed at exposures below the clinical exposure. Changes consisted in irregular thickening of the femoral growth plate, hypocellularity of the bone marrow next to the altered growth plate and alterations of t
