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.

13 NONCLINICAL TOXICOLOGY
 
13.1 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)].

14 CLINICAL STUDIES
 

14.1 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 unacceptable toxicity. Randomization was stratified according to prior use of chemotherapy for advanced or metastatic disease (yes versus no) and lactate dehydrogenase level (normal versus greater than upper limit of normal). Tumor tissue was eva luated for BRAF mutations at a central testing site using a clinical trial assay. Tumor samples from 289 patients (196 patients treated with MEKINIST and 93 chemotherapy-treated patients) were also tested retrospectively using an FDA-approved companion diagnostic test, THxID™-BRAF assay.

The median age for randomized patients was 54 years, 54% were male, >99% were white, and all patients had baseline ECOG performance status of 0 or 1. Most patients had metastatic disease (94%), were Stage M1c (64%), had elevated LDH (36%), no history of brain metastasis (97