Chemical formula: C₂₁H₂₁F₃IN₃O₂ Molecular mass: 531.318 g/mol PubChem compound: 16222096
Cobimetinib is a reversible, selective, allosteric, oral inhibitor that blocks the mitogen-activated protein kinase (MAPK) pathway by targeting the mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK 2 which results in inhibition of phosphorylation of the extracellular signal-regulated kinase (ERK) 1 and ERK 2. Therefore, cobimetinib blocks the cell proliferation induced by the MAPK pathway through inhibition of the MEK1/2 signalling node.
In the preclinical models, the combination of cobimetinib and vemurafenib showed that by simultaneously targeting mutated BRAF V600 proteins and MEK proteins in melanoma cells, the combination of the two products inhibits MAPK pathway reactivation through MEK1/2, resulting in a stronger inhibition of intracellular signalling and decreased tumour cell proliferation.
Following oral dosing of 60 mg in cancer patients, cobimetinib showed a moderate rate of absorption with a median Tmax of 2.4 hours. The mean steady-state Cmax and AUC0-24 were 273 ng/mL and 4340 ng.h/mL respectively. The mean accumulation ratio at steady state was approximately 2.4-fold. Cobimetinib has linear pharmacokinetics in the dose range of ~3.5 mg to 100 mg.
The absolute bioavailability of cobimetinib was 45.9% (90% CI: 39.7%, 53.1%) in healthy subjects. A human mass balance study was conducted in healthy subjects, and showed that cobimetinib was extensively metabolised and eliminated in faeces. The fraction absorbed was ~88% indicating high absorption and first pass metabolism.
The pharmacokinetics of cobimetinib are not altered when administered in the fed state (high-fat meal) compared with the fasted state in healthy subjects. Since food does not alter the pharmacokinetics of cobimetinib, it can be administered with or without food.
Cobimetinib is 94.8% bound to human plasma proteins in vitro. No preferential binding to human red blood cells was observed (blood to plasma ratio 0.93).
The volume of distribution was 1050 L in healthy subjects given an intravenous dose of 2 mg. The apparent volume of distribution was 806 L in cancer patients based on population pharmacokinetic analysis.
Cobimetinib is a substrate of P-gp in vitro. The transport across the blood brain barrier is unknown.
Oxidation by CYP3A and glucuronidation by UGT2B7 appear to be the major pathways of cobimetinib metabolism. Cobimetinib is the predominant moiety in plasma. No oxidative metabolites greater than 10% of total circulating radioactivity or human specific metabolites were observed in plasma. Unchanged medicinal product in faeces and urine accounted for 6.6% and 1.6% of the administered dose, respectively, indicating that cobimetinib is primarily metabolised with minimal renal elimination. In vitro data indicate cobimetinib is not an inhibitor of OAT1, OAT3 or OCT2.
Cobimetinib and its metabolites were characterised in a mass balance study in healthy subjects. On average, 94% of the dose was recovered within 17 days. Cobimetinib was extensively metabolised and eliminated in faeces.
Following intravenous administration of a 2 mg dose of cobimetinib, the mean plasma clearance (CL) was 10.7 L/hr. The mean apparent CL following oral dosing of 60 mg in cancer patients was 13.8 L/hr.
The mean elimination half-life following oral dosing of cobimetinib was 43.6 hours (range: 23.1 to 69.6 hours). Therefore, it may take up to 2 weeks following treatment cessation for cobimetinib to be completely removed from systemic circulation.
Based on a population pharmacokinetic analysis, gender, race, ethnicity, baseline ECOG, mild and moderate renal impairment did not affect the pharmacokinetic of cobimetinib. Baseline age and baseline body weight were identified as statistically significant covariates on cobimetinib clearance and volume of distribution respectively. However, sensitivity analysis suggests neither of these covariates had clinically significant impact on steady state exposure.
Gender does not have an effect on the exposure of cobimetinib, based on a population pharmacokinetic analysis including 210 women and 277 men.
Age does not have an effect on the exposure of cobimetinib, based on a population pharmacokinetic analysis including 133 patients ≥65 years of age.
Based on preclinical data and the human mass balance study, cobimetinib is mainly metabolised, with minimal renal elimination. No formal pharmacokinetic study has been conducted in patients with renal impairment.
A population pharmacokinetic analysis using data from 151 patients with mild renal impairment (creatinine clearance (CRCL) 60 to less than 90 mL/min), 48 patients with moderate renal impairment (CRCL 30 to less than 60 mL/min), and 286 patients with normal renal function (CRCL greater than or equal to 90 mL/min), showed that CRCL had no meaningful influence on exposure of cobimetinib. Mild to moderate renal impairment does not influence cobimetinib exposure based on the population pharmacokinetic analysis. There are minimal data for cobimetinib in patients with severe renal impairment.
The pharmacokinetics of cobimetinib were evaluated in 6 subjects with mild hepatic impairment (Child Pugh A), 6 subjects with moderate hepatic impairment (Child Pugh B), 6 subjects with severe hepatic impairment (Child Pugh C) and 10 healthy subjects. Systemic total cobimetinib exposures after a single dose were similar in subjects with mild or moderate hepatic impairment compared to healthy subjects, while subjects with severe hepatic impairment had lower total cobimetinib exposures (AUC0-∞ geometric mean ratio of 0.69 compared to healthy subjects) which is not considered to be clinically significant. Unbound cobimetinib exposures were similar between subjects with mild and moderate hepatic impairment compared to subjects with normal hepatic function while subjects with severe hepatic impairment had approximately 2-fold higher exposures.
No studies have been conducted to investigate the pharmacokinetics of cobimetinib in paediatric patients.
Carcinogenicity studies have not been conducted with cobimetinib. Standard genotoxicity studies with cobimetinib were negative.
No dedicated fertility studies in animals have been performed with cobimetinib. In toxicology studies, degenerative changes were observed in reproductive tissues including increased apoptosis/necrosis of corpora lutea and seminal vesicle, epididymal and vaginal epithelial cells in rats, and epididymal epithelial cells in dogs. The clinical relevance of this is unknown.
When administered to pregnant rats, cobimetinib caused embryolethality and foetal malformations of the great vessels and skull at systemic exposures similar to human exposure at recommended dose.
Cardiovascular safety of cobimetinib in combination with vemurafenib has not been evaluated in vivo. In vitro, cobimetinib produced moderate hERG ion channel inhibition (IC50=0.5 μM [266 ng/mL]), which is approximately 18 fold higher than peak plasma concentrations (Cmax) at the 60 mg to be marketed dose (unbound Cmax=14 ng/mL [0.03 μM]).
Toxicity studies in rats and dogs identified generally reversible degenerative changes in the bone marrow, gastrointestinal tract, skin, thymus, adrenal gland, liver, spleen, lymph node, kidney, heart, ovary, and vagina at plasma exposures below clinical efficacious levels. Dose limiting toxicities included skin ulcerations, surface exudates, and acanthosis in the rat and chronic active inflammation and degeneration of the oesophagus associated with varying degrees of gastroenteropathy in dogs.
In a repeat dose toxicity study in juvenile rats, cobimetinib systemic exposures were 2 to11 fold higher on post natal day 10 than on post natal day 38 when exposures were similar to those in adult rats. In juvenile rats, cobimetinib administration resulted in similar changes as seen in the pivotal toxicity studies in adults, including reversible degenerative changes in the thymus and liver, decreased spleen and thyroid/parathyroid weights, increased phosphorus, bilirubin and red blood cell mass and decreased triglycerides. Mortality occurred in juvenile animals at a dose (3 mg/kg) which did not lead to mortalities in adult animals.
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