Ontogeny and Sorafenib Metabolism

Abstract

Purpose To investigate the role of ontogeny in sorafenib metabolism to the equipotent active metabolite sorafenib N-oxide. Experimental Design Steady-state pharmacokinetic studies of sorafenib and metabolites were performed in thirty children and young adults (17 males; median age, 9.5 years) receiving sorafenib 150 mg/m2 or 200 mg/m2 twice daily. Sorafenib metabolism was evaluated in vitro at 10 µM using a panel of purified human cytochrome P450 (CYP) enzymes. Sorafenib metabolism and CYP3A4 expression was evaluated in 52 human liver samples from donors ≤ 20 years old. The drug-drug interaction potential between sorafenib and azole antifungal agents was evaluated in vitro and in vivo. Results No age-related differences in sorafenib apparent oral clearance were observed. Mean sorafenib N-oxide metabolite ratio was 0.27±0.14. In children ≤ 10 years of age, boys had approximately 2-fold higher N-oxide ratios than girls (0.40±0.15 versus 0.22±0.12, P = 0.026). Of the CYPs evaluated, sorafenib was exclusively metabolized to sorafenib N-oxide by CYP3A4. A trend for increased N-oxide formation in boys was observed in liver samples, which correlated with CYP3A4 mRNA expression. Posaconazole and voriconazole potently inhibited sorafenib N-oxide formation in vitro, and reduced sorafenib N-oxide formation in 3 children given sorafenib concurrent with azoles. Conclusion We have identified several factors affecting inter-patient variability in sorafenib metabolism to the active N-oxide metabolite including age, sex, and concurrent treatment with azole antifungals. This knowledge may provide important considerations for the clinical use of sorafenib in children and possibly other kinase inhibitors undergoing CYP3A4-mediated metabolism.

Sorafenib Metabolism Is Significantly Altered in the Liver Tumor Tissue of Hepatocellular Carcinoma Patient

“…In addition, we used commercial pooled human microsomes (CHLMs) as a control. In CHLMs, the K m value was 11.48±4.19 µM for oxidation and 2.89±0.29 µM for glucuronidation, which was equal to that reported in the previous publication (12.1±0.71 µM and 3.6±0.22 µM, respectively) [33]. Furthermore, we have measured the UGT1A9 protein content by UPLC-MS/MS.…”

Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation

“…First, sorafenib concentrations can be variable in patients receiving this medication, possibly due to age, gender, and effects of concomitant medications (chemotherapy or CYP3A4 inhibitors) on the metabolism of the drug. 25,26,48 Variability in FLT3 inhibition as assessed by the PIA assay has previously been noted with sorafenib. 26 Second, some The Inhibited group consisted of 14 patients whose P-FLT3 levels were ,15% of baseline at $1 point during the first cycle of therapy.…”

Hepatocellular Shuttling and Recirculation of Sorafenib-Glucuronide Is Dependent on Abcc2, Abcc3, and Oatp1a/1b

“…3C). Ex vivo metabolism studies indicated that, compared to mice and humans (9), rat liver microsomes lack a significant capacity to form SG (Fig. 3D).…”

“…ATP-dependent transport of sorafenib and SG was determined by subtracting AMP-dependent transport from ATP-dependent transport, with both expressed in pmol/min/mg, after normalization for non-specific transport observed in control vesicles. Uptake experiments were carried out at a concentration of 10 µM, which is equivalent to average sorafenib plasma steady-state concentrations achievable in adults and children treated at 400 mg or 200 mg/m 2 twice daily (9, 21). …”

“…Like other orally-administered tyrosine kinase inhibitors, sorafenib displays wide interindividual pharmacokinetic variability, which can significantly affect drug-induced toxicity and possibly efficacy (6, 7). Although the metabolic pathways of sorafenib have been reasonably well established, involving a CYP3A4-mediated route to form sorafenib-N-oxide (8) and a UGT1A9-mediated route to form sorafenib-glucuronide (SG) (9), the primary causes of the pharmacokinetic variability remain unknown (10, 11). It has been suggested that sorafenib undergoes enterohepatic recirculation, a process that involves removal of solutes from blood by uptake into hepatocytes, excretion into bile, and intestinal reabsorption, sometimes accompanied by hepatic conjugation and intestinal deconjugation (12).…”