s 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 trametinib have not been studied in patients with severe renal impairment [see Use in Specific Populations (8.8)].
Pediatrics: No studies have been conducted to eva luate the pharmacokinetics of trametinib in pediatric patients.
Drug Interactions: No formal drug interaction studies have been conducted with trametinib. Trametinib is not a substrate of CYP enzymes or efflux transporters P-gp or BCRP in vitro.
Based on in vitro studies, trametinib is not an inhibitor of CYP450 including CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 or of transporters including OATP1B1, OATP1B3, P-gp, and BCRP at a clinically relevant systemic concentration of 0.04 µM. Trametinib is an inhibitor of CYP2C8 in vitro.
Trametinib is an inducer of CYP3A4 in vitro. Based on cross-study comparisons, oral administration of trametinib 2 mg once daily with everolimus (sensitive CYP3A4 substrate) 5 mg once daily, had no clinically important effect on the AUC and Cmax of everolimus.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with trametinib have not been conducted. Trametinib was not genotoxic in studies eva luating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, and micronuclei in the bone marrow of rats.
Trametinib may impair fertility in humans. In female rats given trametinib for up to 13 weeks, increased follicular cysts and decreased corpora lutea were observed at doses ≥0.016 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC ). In rat and dog toxicity studies up to 13 weeks in duration, there were no treatment effects observed on male reproductive tissues [see Use in Specific Populations (8.6)].
Clinical Studies
BRAF V600E or V600K Mutation-Positive Metastatic Melanoma
The safety and efficacy of Mekinist were eva luated in an international, multi-center, randomized (2:1), open label, active-controlled trial (Trial 1) in 322 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were not permitted to have more than one prior chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not permitted. The primary efficacy outcome measure was progression-free survival (PFS). Patients were randomized to receive Mekinist 2 mg orally once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine 1,000 mg/m2 intravenously every 3 weeks or paclitaxel 175 mg/m2 intravenously every 3 weeks. Treatment continued until disease progression or unacceptabl |
