Pathway Sorafenib Pharmacokinetics

Schematic representation of sorafenib metabolism in human liver cell.
Sorafenib Pharmacokinetics
UGT3A4 UGT1A9 UGT1A1 CYP2C9 CYP2C8 CYP2B6 sorafenib
clickable pathway icons
Reproductions of this diagram can be used with permission from PharmGKB. Request permission

Description

Sorafenib (NEXAVAR®, BAY43-9006) is an oral anti-cancer drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced renal cell carcinoma (RCC), unresectable or metastatic hepatocellular carcinoma (HCC), and locally recurrent or metastatic, progressive and differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment [Article:21374666]. It is also being evaluated in acute myeloid leukemia (AML) and other solid tumors in adults and children. Sorafenib inhibits tumor cell proliferation and angiogenesis via targeting numerous serine/threonine and tyrosine kinases (RAF1, BRAF, VEGFR 1, 2, 3, PDGFR, KIT, FLT3, FGFR1, and RET) in multiple oncogenic signaling pathways [Articles:15466206, 16507829, 17016424, 17470685]. The most common adverse effects associated with sorafenib include hand-foot skin reaction (HFSR), diarrhea, hypertension, rash, fatigue, abdominal pain and nausea [Articles:21898496, 24283303, 27443985, 27106231]. Serious adverse effects (eg. liver failure, myocardial infarction) are rare but may arise in some cases. Adverse events may lead to compromised efficacy due to dose reduction or treatment interruptions. There is high interpatient variability in cumulative drug exposure and responses following sorafenib treatment [Articles:17016424, 17470685, 25641331, 25976912]. In this review, we discuss the clinical pharmacology of sorafenib and highlight genetic variations that may contribute to the diverse pharmacological responses to sorafenib. Better understanding of the factors contributing to the high variability of response to sorafenib should improve the efficacy and safety of the drug, and help select patients who will benefit most from sorafenib therapy.

Pharmacokinetics Sorafenib is a small lipophilic molecule with low-solubility and high permeability. After oral administration, it is rapidly absorbed from the gastrointestinal tract and reaches the liver via the portal vein. Sorafenib reaches peak plasma levels between 1 and 12 hours, with typically longer periods for the fed state, and reaches steady-state concentrations typically around 7 days [Articles:15870716, 16006586, 15613696, 17470685]. It has a relatively long mean half-life ranging from approximately 20 to 48 hours at the 400 mg bid dose. The majority (77%) of sorafenib is eliminated in the feces (51% unchanged) and about 19% is excreted in the urine (mostly as glucuronide conjugates of the parent drug and its metabolites) [Article:16133532]. Full prescribing information about the drug is available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021923s016lbl.pdf.

High interpatient pharmacokinetic variability was observed with multiple dosing of sorafenib. Clinical trials showed that sorafenib exposure (area under the plasma drug concentration-time curve (AUC)) varied from 18.0 –24.0 mg*h/l on day 1 and 47.8 –76.5mg*h/l on the last day of the dosing cycle, and the peak plasma concentrations (Cmax) ranged from 2.3–3.0 mg/l on day 1 and 5.4 –10.0 mg/l on the last day of dosing [Articles:15870716, 16061863, 16006586, 17470685]. The median time to peak plasma concentration (Tmax) varied from 2–12 h. Additionally, sorafenib’s AUC and Cmax values increased less than proportionally with increasing dose [Articles:15870716, 16061863, 16006586, 17470685]. Incidence and severity of sorafenib-induced side effects (eg.HFSR) were also related to cumulative dose and sorafenib exposure level [Articles:19228742, 22912756, 22752067, 24135988]. The underlying mechanisms that led to these variabilities are not fully elucidated, and no validated markers have been found that can predict clinical outcome or tolerability for sorafenib [Articles:22374331, 26420960, 27220960].

Sorafenib is metabolized primarily in the liver via two pathways: phase I oxidation mediated by cytochrome P450 3A4 (CYP3A4), and phase II conjugation mediated by UDP glucuronosyltransferase 1A9 (UGT1A9) [Articles:22513143, 22307138]. Eight metabolites of sorafenib have been identified (M1-8) [Article:19228077]. The main circulating metabolite in the plasma is sorafenib N-oxide (M2) and it is produced through oxidation of sorafenib by CYP3A4 [Article:19733976]. Comprising 9 – 16% of the circulating analytes at steady-state, M2 exhibits an in vitro potency similar to sorafenib [Article:16061863]. M2 also gets further metabolized to N-hydroxymethyl-sorafenib-N-oxide (M1), and glucuronidated to M8 . The metabolite M7 (glucuronide of sorafenib) is produced through glucuronidation of the parent compound by UGT1A9 . Glucuronidation accounts for clearance of about 15% of sorafenib dose in human, while oxidation accounts for only 5% [Article:16133532]. Among the metabolites of sorafenib, M2, M4 (demethylation), and M5 (oxidative metabolite) were found to inhibit Vascular Endothelial Growth Factor Receptor (VEGFR) signaling pathway, Platelet-Derived Growth Factor Receptor (PDGFR) signaling pathway and members of the Mitogen-Activated Protein Kinase (MAPK) pathway .

Since the metabolism of sorafenib occurs through the CYP3A4 and UGT1A9 pathways, induction or inhibition of these pathways may affect the pharmacokinetics and effectiveness of sorafenib. Administration of the drug with CYP3A4 inducers, such as rifampin, St. John’s Wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone, has been shown to increase the metabolism of sorafenib and decrease exposure [Article:17189398]. In contrast, administration of the drug with an inhibitor of CYP3A4, ketoconazole, did not significantly influence sorafenib exposure in healthy volunteers receiving a single dose of sorafenib, nor did it affect safety or tolerability of sorafenib [Articles:16133532, 22513143]. Though not a substrate for CYP2B6, CYP2C8, CYP2C9 and UGT1A1, sorafenib has been shown to inhibit their activities in vitro [Articles:19228077, 22307138]. The clinical significance of this inhibition is not clear, and drugs that are metabolized by these enzymes should be used with caution in patients receiving sorafenib due to a potential risk of drug interactions.

In addition to differences in metabolizing enzymes, inter-individual differences in hepatic transporters may also contribute to the substantial pharmacokinetic variability observed with sorafenib. In vitro and preclinical studies demonstrated that the hepatic uptake of sorafenib and its metabolites is mediated in part by organic cation transporter-1 (OCT1, encoded by gene SLC22A1) [Articles:23532667, 23482500, 27053087, 26769852, 28178663] and by organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3, encoded by gene SLCO1B1, SLCO1B3) [Articles:23532667, 23482500, 23340295]. Sorafenib also showed moderate affinity for the efflux transporter P-glycoprotein (p-gp, encoded by gene ABCB1) and breast cancer resistance protein (BCRP, encoded by gene ABCG2) [Articles:19773380, 20413726, 20446917, 20103600, 19626587, 20952483]. Functional differences of both the influx and efflux transporters (either due to genetic variation or co-medication) may affect systemic exposure and response of sorafenib. Moreover, intra-tumoral OCT1 mRNA expression has been shown to be a significant positive prognostic factor in hepatocellular carcinoma patients treated with sorafenib [Article:26872727].

Authors: Li Gong, Marilyn M. Giacomini, Craig P. Giacomini.
Citation:
Gong Li, Giacomini Marilyn M, Giacomini Craig, Maitland Michael L, Altman Russ B, Klein Teri E . "PharmGKB summary: sorafenib pathways" Pharmacogenetics and genomics (2017).
History:
Therapeutic Categories:
  • Anticancer agents

Entities in the Pathway

Genes (6)

Drugs/Drug Classes (1)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
CYP2B6 CYP2B6 sorafenib 19228077
CYP2C8 CYP2C8 sorafenib 19228077
CYP2C9 CYP2C9 sorafenib 19228077
M3 M1 16133532
M4 M5 16133532
Pyridine N-oxide (M2) M1 16133532
sorafenib glucuronide of sorafinib UGT1A9 16133532, 22307138
sorafenib M3 16133532
sorafenib M4 16133532
UGT1A1 UGT1A1 sorafenib 19228077, 22307138
sorafenib Pyridine N-oxide (M2) CYP3A4 19228077
Pyridine N-oxide (M2) glucuronide of M2 19228077

Download data in TSV format . Other formats are available on the Downloads/LinkOuts tab.

Related Pathways