Chemical formula: C₂₂H₂₇ClFN₇O₄S Molecular mass: 540.01 g/mol PubChem compound: 50922675
Encorafenib is a potent and highly selective ATP-competitive small molecule RAF kinase inhibitor. The half maximal inhibitory concentration (IC50) of encorafenib against BRAF V600E, BRAF and CRAF enzymes was determined to be 0.35, 0.47 and 0.30 nM, respectively. The encorafenib dissociation half-life was >30 hours and resulted in prolonged pERK inhibition. Encorafenib suppresses the RAF/MEK/ERK pathway in tumour cells expressing several mutated forms of BRAF kinase (V600E, D and K). Specifically, encorafenib inhibits in vitro and in vivo BRAF V600E, D and K mutant melanoma cell growth and BRAF V600E mutant colorectal cancer cell growth. Encorafenib does not inhibit RAF/MEK/ERK signalling in cells expressing wild-type BRAF.
Encorafenib and binimetinib (a MEK inhibitor) both inhibit the MAPK pathway, resulting in higher anti-tumour activity, compared to treatment with either drug alone.
One of the main mechanisms of resistance of BRAF-mutant CRC to RAF inhibitors has been identified as the re-activation of EGFR with bypassing signal transduction via BRAF. Combinations of a BRAF inhibitor, e.g. encorafenib and agents targeting EGFR, e.g. cetuximab have shown to improve anti-tumour efficacy in non-clinical models.
The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumours. The pharmacokinetics of encorafenib have been shown to be approximatively dose linear after single and multiples doses. After repeat once-daily dosing, steady-state conditions were reached within 15 days. The accumulation ratio of approximately 0.5 is likely due to auto-induction of CYP3A4. The inter-subject variability (CV%) of AUC is ranged from 12.3% to 68.9%.
After oral administration, encorafenib is rapidly absorbed with a median Tmax of 1.5 to 2 hours. Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, at least 86% of the encorafenib dose was absorbed. Administration of a single 100 mg dose of encorafenib with a high-fat, high-calorie meal decreased the Cmax by 36%, while the AUC was unchanged. A drug interaction study in healthy subjects indicated the extent of encorafenib exposure was not altered in the presence of a gastric pH-altering agent (rabeprazole).
Encorafenib is moderately (86.1%) bound to human plasma proteins in vitro. Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, the mean (SD) blood-to-plasma concentration ratio is 0.58 (0.02) and the mean (CV%) apparent volume of distribution (Vz/F) of encorafenib is 226 L (32.7%).
Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, metabolism was found to be the major clearance pathway for encorafenib (approximately 88% of the recovered radioactive dose). The predominant biotransformation reaction of encorafenib was N-dealkylation. Other major metabolic pathways involved hydroxylation, carbamate hydrolysis, indirect glucuronidation and glucose conjugate formation.
Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, radioactivity was eliminated equally in both the faeces and urine (mean of 47.2%). In urine, 1.8% of the radioactivity was excreted as encorafenib. The mean (CV%) apparent clearance (CL/F) of encorafenib was 27.9 L/h (9.15%). The median (range) encorafenib terminal half-life (T1/2) was 6.32 h (3.74 to 8.09 h).
No drug drug interaction was evidenced between encorafenib and cetuximab.
Encorafenib is metabolised by CYP3A4, CYP2C19 and CYP2D6. In vitro, CYP3A4 was predicted to be the major enzyme contributing to total oxidative clearance of encorafenib in human liver microsomes (~83.3%), followed by CYP2C19 and CYP2D6 (~16.0% and 0.71%, respectively). The effect of co-administering a strong CYP3A4 inducer on encorafenib exposure has not been studied in a dedicated trial. Repeat dose administration of encorafenib 450 mg once daily and binimetinib 45 mg twice daily in melanoma patients with modafinil, a moderate CYP3A4 inducer, decreased encorafenib steady-state AUC by 24% and Cmax by 20%, compared to encorafenib alone.
In vitro experiments indicate encorafenib is a relatively potent reversible inhibitor of UGT1A1, CYP2B6, CYP2C9 and CYP3A4/5, as well as a time-dependent inhibitor of CYP3A4. Encorafenib induced CYP1A2, CYP2B6, CYP2C9 and CYP3A4 in human primary hepatocytes.
Repeat dose administration of encorafenib 450 mg once daily and binimetinib 45 mg twice daily in melanoma patients with a single dose of CYP probe substrate cocktail reduced midazolam 2 mg (CYP3A4 substrate) AUC by 82% and Cmax by 74%. It decreased omeprazole 20 mg (CYP2C19 substrate) AUC by 17% and did not change Cmax and increased caffeine 50 mg (CYP1A2 substrate) AUC by 27% and Cmax by 13%. It decreased the ratio of losartan metabolite E3174 to losartan (CYP2C9 substrate) concentrations in urine by 28% and did not change the ratio of dextromethorphan metabolite (dextrorphan) to dextromethorphan (CYP2D6 substrate) concentrations in urine. These results indicate strong induction of CYP3A4, mild inhibition of CYP1A2 and no impact on pharmacokinetics of CYP2C19 substrates. From the urinary data, the inhibitory potency on CYP2C9 and CYP2D6 cannot be finally concluded. No data are available for CYP2D6 poor metabolisers.
A single dose of encorafenib 450 mg and binimetinib 45 mg reduced bupropion 75 mg (CYP2B6 substrate) AUC and Cmax by ≤25%. Repeated administration of encorafenib 450 mg daily and binimetinib 45 mg twice daily reduced bupropion AUC and Cmax by 26 % and increased the AUC of the active metabolite hydroxybupropion by 49% indicating mild induction.
For co-administration with UGT1A1 substrates that undergo gut extraction, a minor to moderate interaction is expected. While binimetinib is a UGT1A1 substrate, it does not undergo gut extraction and therefore no DDI with encorafenib is expected. Additionally, no differences in exposure have been observed clinically when binimetinib is co-administered with encorafenib.
Encorafenib was found to be a substrate of the P-glycoprotein (P-gp) transporters. Inhibition of P-gp is unlikely to result in a clinically important increase in encorafenib concentrations as encorafenib exhibits high intrinsic permeability. The involvement of several uptake transporter families (OCT1, OATP1B1, OATP1B3 and OATPB1) was investigated in vitro using relevant transporter inhibitors. The data suggest that hepatic uptake transporters are not involved in encorafenib distribution into primary human hepatocytes.
Repeated administration of encorafenib 450 mg once daily and binimetinib 45 mg twice daily with a single dose of rosuvastatin (a OATP1B1, OATP1B3 and BCRP substrate) increased rosuvastatin Cmax by 2.7-fold and AUC by 1.6-fold indicating a mild inhibition of OATP1B1, OATP1B3 and/or BCRP transporters.
In vitro, encorafenib inhibited the hepatic transporter OCT1, but is unlikely to be an effective inhibitor clinically. Based on in vitro studies, there is potential for encorafenib to inhibit renal transporters OCT2, OAT1, OAT3 at clinical concentrations. In addition, encorafenib may inhibit P-gp in the gut at the expected clinical concentrations.
Based on a population pharmacokinetic analysis, age was found to be a significant covariate on encorafenib volume of distribution, but with high variability. Given the small magnitude of these changes and high variability, these are unlikely to be clinically meaningful, and no dose adjustments are needed for elderly patients.
Based on a population pharmacokinetic analysis gender was not found to be a significant model covariate on clearance or volume of distribution. As a result, no major changes in encorafenib exposure are expected based upon gender. Body weight Based on a population pharmacokinetic analysis, body weight was found to be a significant model covariate on clearance and volume of distribution. However, given the small magnitude of change in clearance and the high variability in the predicted volume of distribution in the model, weight is unlikely to have a clinically relevant influence on the exposition of encorafenib.
There are no clinically relevant differences in encorafenib PK between Asians and non Asians. There are insufficient data to evaluate potential differences in the exposure of encorafenib in other races or ethnicity.
Results from a dedicated clinical study indicate a 25% higher total encorafenib exposures in patients with mild hepatic impairment (Child-Pugh Class A) compared with subjects with normal liver function. This translates into a 55% increase of the unbound encorafenib exposure.
The pharmacokinetics of encorafenib has not been evaluated clinically in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. As encorafenib is primarily metabolised and eliminated via the liver, based on PBPK modelling, patients with moderate to severe hepatic impairment may have greater increases in exposure than patients with mild hepatic 33 impairment. No dosing recommendation can be made in patients with moderate or severe hepatic impairment.
Encorafenib undergoes minimal renal elimination. No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of encorafenib.
In a population pharmacokinetic analysis, no clear trend in encorafenib CL/F was observed in patients with mild (eGFR 60 to 90 mL/min/1.73 m²) or moderate (eGFR 30 to 59 mL/min/1.73 m²) renal impairment compared with subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²). A small decrease in CL/F (≤5%) was predicted for patients with mild and moderate renal impairment, which is unlikely to be clinically relevant. The pharmacokinetics of encorafenib have not been studied in patients with severe renal impairment.
In the 4-week and 13-week rat toxicity studies, clinical signs, reduced body weight reduced epididymides and prostate weights and microscopic findings in testes, epididymides, stomach and skin were noted. Partial reversibility of these findings was noted after a 4-week recovery period. No NOAEL could be established for the 4-week study. The NOAEL determined in the 13-week study was more than 10-times human therapeutic exposures.
In the 4-week and 13-week monkey toxicity study, isolated/sporadic episodes of emesis and diarrhoea as well as ophthalmic lesions were observed at slightly above human therapeutic exposures. Ophthalmic lesions were partially reversible and consisted of a separation or detachment in the retina between the outer rods and cones layer and retinal pigmented epithelium at the central macula at the fovea. This observation was similar to that described in humans as central serous-like chorioretinopathy or central serous retinopathy.
Encorafenib was not genotoxic.
Fertility studies were not conducted with encorafenib. In the 13-week rat toxicology studies, encorafenib treatment at 6 mg/kg/d (dose level more than 5 times the human exposure at the therapeutic dose) resulted in decreased testes and epididymis weights with tubular degeneration and oligospermia. In the 13-week study, partial reversibility was noted at the highest dose level (60 mg/kg/d).
The embryo-foetal development study in rats indicated that encorafenib induced foetal toxicity with lower foetal weights and delays in skeletal development.
The embryo-foetal development study in rabbits indicated that encorafenib induced foetal toxicity with lower foetal weights and transitory changes in skeletal development. Dilatation of the aortic arc was observed in some foetuses.
Encorafenib was phototoxic in an in vitro 3T3 Neutral Red Uptake Test. Encorafenib was not a sensitiser in the in vivo mouse sensitization assay. Collectively, these data indicate that encorafenib has a risk of phototoxic potential and minimal risk for sensitization at therapeutic doses in patients.
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