an Medicines Agency has deferred the obligation to submit the results of studies with binimetinib in one or more subsets of the paediatric population in melanoma (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
The pharmacokinetics of binimetinib were studied in healthy subjects and patients with solid tumours and advanced and unresectable or metastatic cutaneous melanoma. After repeat twice-daily dosing concomitantly with encorafenib, steady-state conditions for binimetinib were reached within 15 days with no major accumulation. The mean (CV %) Cmax,ss was 654 ng/mL (34.7 %) and mean AUCss was 2.35 ug.h/mL (28.0 %) in combination with encorafenib as estimated by population PK modelling. Binimetinib pharmacokinetics have been shown to be approximately dose-linear.
Absorption
After oral administration, binimetinib is rapidly absorbed with a median Tmax of 1.5 hours. Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, at least 50 % of the binimetinib dose was absorbed. Administration of a single 45 mg dose of binimetinib with a high-fat, high-calorie meal decreased the maximum binimetinib concentration (Cmax) by 17 %, while the area under the concentration-time curve (AUC) was unchanged. A drug interaction study in healthy subjects indicated that the extent of binimetinib exposure is not altered in the presence of a gastric pH-altering agent (rabeprazole).
Distribution
Binimetinib is 97.2 % bound to human plasma proteins in vitro. Binimetinib is more distributed in plasma than blood. In humans, the blood-to-plasma ratio is 0.718. Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, the apparent volume of distribution (Vz/F) of binimetinib is 374 L.
Biotransformation
Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, the primary biotransformation pathways of binimetinib observed in humans include glucuronidation, N- dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The maximum contribution of direct glucuronidation to the clearance of binimetinib was estimated to have been 61.2 %. Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, approximately 60 % of the circulating radioactivity AUC in plasma was attributable to binimetinib. In vitro, CYP1A2 and CYP2C19 catalyse the formation of the active metabolite, which represents less than 20 % of the binimetinib exposure clinically.
Elimination
Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, a mean of 62.3 % of the radioactivity was eliminated in the feces while 31.4 % was eliminated in the urine. In urine, 6.5 % of the radioactivity was excreted as binimetinib. The mean (CV %) apparent clearance (CL/F) of binimetinib was 28.2 L/h (17.5 %). The median (range) binimetinib terminal half-life (TJ/2) was 8.66 h (8.10 to 13.6 h).
Medicinal product interactions
Effect of UGT1A1 inducers or inhibitors on binimetinib
Binimetinib is primarily metabolised through UGT1A1 mediated glucuronidation. In clinical study sub-analysis, however, there was no apparent relationship observed between binimetinib exposure and UGT1A1 mutation status. In addition, simulations to investigate the effect of 400 mg atazanavir (UGT1A1 inhibitor) on the exposure of 45 mg binimetinib predicted similar binimetinib Cmax in the presence or absence of atazanavir. Therefore, the extent of drug inter
