Chemical formula: C₂₁H₁₅ClF₄N₄O₃ Molecular mass: 482.815 g/mol PubChem compound: 11167602
Regorafenib inhibits mutated KIT, a major oncogenic driver in gastrointestinal stromal tumours, and thereby blocks tumour cell proliferation.
Regorafenib is an oral tumour deactivation agent that potently blocks multiple protein kinases, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), metastasis (VEGFR3, PDGFR, FGFR) and tumour immunity (CSF1R).
In preclinical studies regorafenib has demonstrated potent antitumour activity in a broad spectrum of tumour models including colorectal, gastrointestinal stromal and hepatocellular tumour models which is likely mediated by its anti-angiogenic and anti-proliferative effects. In addition, regorafenib reduced the levels of tumour associated macrophages and has shown anti-metastatic effects in vivo. Major human metabolites (M-2 and M-5) exhibited similar efficacies, compared to regorafenib in in vitro and in vivo models.
Regorafenib reaches mean peak plasma levels of about 2.5 mg/l at about 3 to 4 hours after a single oral dose of 160 mg given as 4 tablets each containing 40 mg. Following single doses of 60 mg or 100 mg, the average relative bioavailability of tablets compared to an oral solution was 69% and 83%, respectively.
The concentrations of regorafenib and its major pharmacologically active metabolites (M-2 and M-5) were highest when given after a low-fat (light) breakfast, compared to either a high-fat breakfast or fasting condition. The exposure for regorafenib was increased by 48% when administered with a high-fat breakfast, and 36% when administered with a low fat breakfast, compared to fasting. The exposure of metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) is higher when regorafenib is given with a low fat breakfast, compared to fasting condition and lower when given with a high fat meal, compared to fasting condition.
Plasma concentration-time profiles for regorafenib as well as for the major circulating metabolites showed multiple peaks across the 24-hour dosing interval, which are attributed to enterohepatic circulation. In vitro protein binding of regorafenib to human plasma proteins is high (99.5%). In vitro protein binding of M-2 and M-5 is higher (99.8% and 99.95%, respectively) than that of regorafenib. Metabolites M-2 and M-5 are weak substrates of P-gp. Metabolite M-5 is a weak BCRP-substrate.
Regorafenib is metabolized primarily in the liver by oxidative metabolism mediated by CYP3A4, as well as by glucuronidation mediated by UGT1A9. Two major and six minor metabolites of regorafenib have been identified in plasma. The main circulating metabolites of regorafenib in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), which are pharmacologically active and have similar concentrations as regorafenib at steady state. M-2 is further metabolised by oxidative metabolism mediated by CYP3A4, as well as by glucuronidation mediated by UGT1A9. Metabolites may be reduced or hydrolysed in the gastrointestinal tract by microbial flora, allowing reabsorption of the unconjugated active substance and metabolites (enterohepatic circulation).
Following oral administration, mean elimination half-life for regorafenib and its metabolite M-2 in plasma ranges from 20 to 30 hours in different studies. The mean elimination half-life for the metabolite M-5 is approximately 60 hours (range from 40 to 100 hours).
Approximately 90% of the radioactive dose was recovered within 12 days after administration, with about 71% of the dose excreted in faeces (47% as parent compound, 24% as metabolites), and about 19% of the dose excreted in urine as glucuronides. Urinary excretion of glucuronides decreased below 10% under steady-state conditions. Parent compound found in faeces could be derived from intestinal degradation of glucuronides or reduction of metabolite M-2 (N-oxide), as well as unabsorbed regorafenib. M-5 may be reduced to M-4 in the gastrointestinal tract by microbial flora, allowing reabsorption of M-4 (enterohepatic circulation). M-5 is finally excreted via M-4 as M-6 (carboxylic acid) in faeces.
Systemic exposure of regorafenib at steady-state increases dose proportionally up to 60 mg and less than proportionally at doses greater than 60 mg. Accumulation of regorafenib at steady state results in about a 2-fold increase in plasma concentrations, which is consistent with the elimination half-life and dosing frequency. At steady state, regorafenib reaches mean peak plasma levels of about 3.9 mg/L (8.1 micromolar) after oral administration of 160 mg regorafenib and the peak-to-trough ratio of mean plasma concentrations is less than 2. Both metabolites, M-2 and M-5, exhibit non-linear accumulation, which might be caused by enterohepatic recycling or saturation of the UGT1A9 pathway. Whereas plasma concentrations of M-2 and M-5 after a single dose of regorafenib are much lower than those of parent compound, steady-state plasma concentrations of M-2 and M-5 are comparable to those of regorafenib.
The exposure of regorafenib and its metabolites M-2 and M-5 is comparable in patients with mild hepatic impairment (Child-Pugh A) and patients with normal hepatic function. Limited data in patients with moderate hepatic impairment (Child-Pugh B) indicate similar exposure, compared to patients with normal hepatic function after a single 100 mg dose of regorafenib. There are no data for patients with Child-Pugh C (severe) hepatic impairment. Regorafenib is mainly eliminated via the liver, and exposure might be increased in this patient population.
Available clinical data and physiology-based pharmacokinetic modelling indicate similar steady-state exposure of regorafenib and its metabolites M-2 and M-5 in patients with mild or moderate renal impairment, compared to patients with normal renal function. In patients with severe renal impairment compared to patients with normal renal function, regorafenib exposure was similar while exposure to M-2 and M-5 was decreased by about 30% under steady-state conditions, which is not considered clinically relevant.
The pharmacokinetics of regorafenib has not been studied in patients with end-stage renal disease. However, physiology-based pharmacokinetic modelling does not predict any relevant change in exposure in these patients.
Age did not affect the regorafenib pharmacokinetics over the studied age range (29-85 years).
The pharmacokinetics of regorafenib is not influenced by gender.
The exposure of regorafenib in various Asian populations (Chinese, Japanese, Korean) is within the same range as seen in Caucasians.
No QTc prolonging effects were observed after administration of 160 mg regorafenib at steady state in a dedicated QT study in male and female cancer patients.
After repeated dosing to mice, rats and dogs, adverse effects were observed in a number of organs, primarily in the kidneys, liver, digestive tract, thyroid gland, lympho-/haematopoietic system, endocrine system, reproductive system and skin. A slightly increased incidence of thickening of the atrioventricular valves of the heart was seen in the 26 week repeat-dose toxicity study in rats. This may be due to acceleration of an age-related physiological process. These effects occurred at systemic exposures in the range of or below the anticipated human exposure (based on AUC comparison).
Alterations of teeth and bones and adverse effects in the reproductive system were more pronounced in young and growing animals as well as in juvenile rats and indicate a potential risk for children and adolescents.
Specific studies on fertility have not been performed. However, a potential of regorafenib to adversely affect male and female reproduction has to be considered based on morphological changes in the testes, ovaries, and the uterus observed after repeated dosing in rats and dogs at exposures below the anticipated human exposure (based on AUC comparison). The observed changes were only partially reversible.
An effect of regorafenib on intrauterine development was shown in rabbits at exposures below the anticipated human exposure (based on AUC comparison). Main findings consisted of malformations of the urinary system, the heart and major vessels, and the skeleton.
There was no indication for a genotoxic potential of regorafenib tested in standard assays in vitro and in vivo in mice.
Studies on the carcinogenic potential of regorafenib have not been performed.
Environmental risk assessment studies have shown that regorafenib has the potential to be persistent, bioaccumulative and toxic to the environment and may pose a risk to the surface water and to the sediment compartment.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
