12.3 Pharmacokinetics
The pharmacokinetics (PK) of trametinib were characterized following single- and repeat-oral administration in patients with solid tumors and BRAF V600 mutation-positive metastatic melanoma.

Absorption: After oral administration, the median time to achieve peak plasma concentrations (Tmax) is 1.5 hours post-dose. The mean absolute bioavailability of a single 2-mg oral dose of trametinib tablet is 72%. The increase in Cmax was dose proportional after a single dose of 0.125 to 10 mg while the increase in AUC was greater than dose proportional. After repeat doses of 0.125 to 4 mg daily, both Cmax and AUC increase proportionally with dose. Inter-subject variability in AUC and Cmax at steady state is 22% and 28%, respectively.

Administration of a single dose of trametinib with a high-fat, high-calorie meal decreased AUC by 24%, Cmax by 70%, and delayed Tmax by approximately 4 hours as compared to fasted conditions [see Dosage and Administration (2.2)].

Distribution: Trametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 214 L.

Metabolism: Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases.

Following a single dose of [14C]-trametinib, approximately 50% of circulating radioactivity is represented as the parent compound. However, based on metabolite profiling after repeat dosing of trametinib, ≥75% of drug-related material in plasma is the parent compound.

Elimination: The estimated elimination half-life based on the population PK model is 3.9 to 4.8 days. The apparent clearance is 4.9 L/h.

Following oral administration of [14C]-trametinib, >80% of excreted radioactivity was recovered in the feces while <20% of excreted radioactivity was recovered in the urine with <0.1% of the excreted dose as parent.

Specific Populations: Based on a population pharmacokinetic analysis, age, gender, and body weight do not have a clinically important effect on the exposure of trametinib. There are insufficient data to eva luate potential differences in the exposure of trametinib by race or ethnicity.

Hepatic Impairment: Based on a population pharmacokinetic analysis in 64 patients with mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1.0-1.5 x ULN and any AST), mild hepatic impairment has no clinically important effect on the systemic exposure of trametinib. The pharmacokinetics of trametinib have not been studied in patients with moderate or severe hepatic impairment [see Use in Specific Populations (8.7)].

Renal Impairment: As renal excretion of trametinib is low (<20%), renal impairment is unlikely to have a clinically important effect on the exposure of trametinib. Based on a population PK analysis in 223 patients with mild renal impairment (GFR 60 to 89 mL/min/1.73 m2) and 35 patients with moderate renal impairment (GFR 30 to 59 mL/min/1.73 m2), mild and moderate renal impairment have no clinically important effects on the systemic exposure of trametinib. The PK of tramet