Chemical formula: C₂₆H₂₃FIN₅O₄ Molecular mass: 615.395 g/mol PubChem compound: 11707110
Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins are components of the extracellular signal-related kinase (ERK) pathway. In human cancers, this pathway is often activated by mutated forms of BRAF which activates MEK. Trametinib inhibits activation of MEK by BRAF and inhibits MEK kinase activity.
Trametinib inhibits growth of BRAF V600 mutant melanoma cell lines and demonstrates anti-tumour effects in BRAF V600 mutant melanoma animal models.
Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutive activation of the RAS/RAF/MEK/ERK pathway.
Thus, trametinib and dabrafenib inhibit two kinases in this pathway, MEK and RAF, and therefore the combination provides concomitant inhibition of the pathway. The combination of trametinib with dabrafenib has shown anti-tumour activity in BRAF V600 mutation-positive cancer cell lines in vitro and delays the emergence of resistance in vivo in BRAF V600 mutation-positive xenografts.
Trametinib suppressed levels of phosphorylated ERK in BRAF mutant melanoma tumour cell lines and melanoma xenograft models.
In patients with BRAF and NRAS mutation positive melanoma, administration of trametinib resulted in dose-dependent changes in tumour biomarkers including inhibition of phosphorylated ERK, inhibition of Ki67 (a marker of cell proliferation), and increases in p27 (a marker of apoptosis). The mean trametinib concentrations observed following repeat dose administration of 2 mg once daily exceeds the preclinical target concentration over the 24-hr dosing interval, thereby providing sustained inhibition of the MEK pathway.
The pharmacokinetic properties of trametinib have mostly been determined in adult patients using the solid (tablet) formulation. The pharmacokinetics of trametinib following single or repeat weight-adjusted dosing were also evaluated in 244 paediatric patients. Pharmacokinetic characteristics (drug absorption rate and drug clearance) of trametinib in paediatric patients were comparable to those of adults. Weight was found to influence trametinib oral clearance, while age did not. The pharmacokinetic exposures of trametinib at the recommended weight-adjusted dose in paediatric patients were within range of those observed in adults.
Trametinib is absorbed orally with median time to achieve peak concentrations of 1.5 hours post-dose. The mean absolute bioavailability of a single 2 mg tablet dose is 72% relative to an intravenous (IV) microdose. The increase in exposure (Cmax and AUC) was dose-proportional following repeat dosing. Following administration of 2 mg once daily, steady-state geometric mean Cmax, AUC(0-τ) and predose concentration were 22.2 ng/ml, 370 ng*hr/ml and 12.1 ng/ml, respectively with a low peak:trough ratio (1.8). Inter-subject variability at steady state was low (<28%).
Trametinib accumulates with repeat daily dosing with a mean accumulation ratio of 6.0 at 2 mg once daily dose. Steady state was achieved by Day 15.
Administration of a single dose of trametinib with a high-fat, high-calorie meal resulted in a 70% and 10% decrease in Cmax and AUC, respectively compared to fasted conditions.
The trametinib oral solution was rapidly absorbed with a median time to achieve peak plasma concentration (Tmax) of 1 hour post-dose. The mean absolute oral bioavailability of the trametinib tablets was 72%. In a relative bioavailability study comparing the oral solution formulation and the tablet formulation after single-dose administration in the fasted state in adults, administration of the oral solution formulation resulted in a 12%, 10% and 71% higher AUC(0-inf), AUC(0-last) and Cmax respectively as compared to the tablet formulation.
Trametinib exposure increased in a dose-proportional manner between 0.125 mg and 4 mg following repeat once-daily dosing.
In the pivotal paediatric study, steady-state geometric mean (CV) Cmax and AUCtau were 22.7 ng/ml (41.1) and 339 ng*hr/ml (22.2%) in the LGG cohort and 21.3 ng/ml (36.3%) and 307 ng*hr/ml (22.8%) in the HGG cohort.
Trametinib accumulates with repeat daily dosing. A mean accumulation ratio of 6.0 was observed for the tablet formulation at 2 mg once-daily dose. Steady state was achieved by Day 15.
The impact of food on the pharmacokinetics of the reconstituted oral solution has not been investigated. Administration of a single dose of trametinib (tablet formulation) with a high-fat, highcalorie meal resulted in a 70% and 10% decrease in Cmax and AUC, respectively, compared to fasted conditions.
Binding of trametinib to human plasma proteins is 97.4%. Trametinib has a volume of distribution of approximately 1200 L determined following administration of a 5 g intravenous microdose.
In vitro and in vivo studies demonstrated that trametinib is metabolised predominantly via deacetylation alone or in combination with mono-oxygenation. The deacetylated metabolite was further metabolised by glucuronidation. CYP3A4 oxidation is considered a minor pathway of metabolism. The deacetylation is mediated by the carboxyl-esterases 1b, 1c and 2, with possible contributions by other hydrolytic enzymes.
Following single and repeated doses of trametinib, trametinib as parent is the main circulating component in plasma.
Mean terminal half-life of trametinib is 127 hours (5.3 days) after single-dose administration. The apparent clearance of trametinib in paediatric patients (median body weight: 32.85 kg) was 3.44 L/h (CV of 20%).
Total dose recovery was low after a 10-day collection period (<50%) following administration of a single oral dose of radiolabelled trametinib as a solution, due to the long elimination half-life. Trametinib-related material was excreted predominantly in the faeces (>80% of recovered radioactivity) and to a minor extent in urine (≤19%). Less than 0.1% of the excreted dose was recovered as parent in urine.
In vitro and in vivo data suggest that trametinib is unlikely to affect the pharmacokinetics of other medicinal products. Based on in vitro studies, trametinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2D6 and CYP3A4. Based on in vitro studies, trametinib is an inhibitor of CYP2C8, CYP2C9 and CYP2C19, an inducer of CYP3A4 and an inhibitor of the transporters OAT1, OAT3, OCT2, MATE1, OATP1B1, OATP1B3, P-gp and BCRP. However, based on the low dose and low clinical systemic exposure relative to the in vitro potency of inhibition or induction values, trametinib is not considered to be an in vivo inhibitor or inducer of these enzymes or transporters, although transient inhibition of BCRP substrates in the gut may occur.
In vivo and in vitro data suggest that the pharmacokinetics of trametinib are unlikely to be affected by other medicinal products. Trametinib is not a substrate of CYP enzymes or of the transporters BCRP, OATP1B1, OATP1B3, OATP2B1, OCT1, MRP2 and MATE1. Trametinib is an in vitro substrate of BSEP and the efflux transporter P-gp. Although trametinib exposure is unlikely to be affected by inhibition of BSEP, increased levels of trametinib upon strong inhibition of hepatic P-gp cannot be excluded.
The effect of repeat-dose trametinib on the steady-state pharmacokinetics of combination oral contraceptives, norethindrone and ethinyl estradiol, was assessed in a clinical study that consisted of 19 female patients with solid tumours. Norethindrone exposure increased by 20% and ethinyl estradiol exposure was similar when co-administered with trametinib. Based on these results, no loss of efficacy of hormonal contraceptives is expected when co-administered with trametinib.
Population pharmacokinetic analyses and data from a clinical pharmacology study in adult patients with normal hepatic function or with mild, moderate or severe bilirubin and/or AST elevations (based on National Cancer Institute [NCI] classification) indicate that hepatic function does not significantly affect trametinib oral clearance.
Renal impairment is unlikely to have a clinically relevant effect on trametinib pharmacokinetics given the low renal excretion of trametinib. The pharmacokinetics of trametinib were characterised in 223 adult patients enrolled in clinical studies with trametinib who had mild renal impairment and 35 adult patients with moderate renal impairment using a population pharmacokinetic analysis. Mild and moderate renal impairment had no effect on trametinib exposure (<6% for either group). No data are available in patients with severe renal impairment.
There are insufficient data to evaluate the potential effect of race on trametinib pharmacokinetics as clinical experience is limited to Caucasians.
Based on a population pharmacokinetic analysis, gender and body weight were found to influence trametinib oral clearance. Although smaller female subjects are predicted to have higher exposure than heavier male subjects, these differences are unlikely to be clinically relevant and no dosage adjustment is warranted.
Carcinogenicity studies with trametinib have not been conducted. Trametinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells and micronuclei in the bone marrow of rats.
Trametinib may impair female fertility in humans, as in repeat-dose studies, increases in cystic follicles and decreases in corpora lutea were observed in female rats at exposures below the human clinical exposure based on AUC.
Additionally, in juvenile rats given trametinib, decreased ovarian weights, slight delays in hallmarks of female sexual maturation (vaginal opening and increased incidence of prominent terminal end buds within the mammary gland) and slight hypertrophy of the surface epithelium of the uterus were observed. All of these effects were reversible following an off-treatment period and attributable to pharmacology. However, in rat and dog toxicity studies up to 13 weeks in duration, there were no treatment effects observed in male reproductive tissues.
In embryo-foetal developmental toxicity studies in rats and rabbits, trametinib induced maternal and developmental toxicity. In rats, decreased foetal weights and increased post-implantation loss were seen at exposures below or slightly above the human clinical exposure based on AUC. In an embryofoetal developmental toxicity study with rabbits, decreased foetal body weight, increased abortions, increased incidence of incomplete ossification and skeletal malformations were seen at sub-clinical exposures based on AUC.
In repeat-dose studies the effects seen after trametinib exposure are found mainly in the skin, gastrointestinal tract, haematological system, bone and liver. Most of the findings are reversible after drug-free recovery. In rats, hepatocellular necrosis and transaminase elevations were seen after 8 weeks at ≥0.062 mg/kg/day (approximately 0.8 times human clinical exposure based on AUC).
In mice, lower heart rate, heart weight and left ventricular function were observed without cardiac histopathology after 3 weeks at ≥0.25 mg/kg/day trametinib (approximately 3 times human clinical exposure based on AUC) for up to 3 weeks. In adult rats, mineralisation of multiple organs was associated with increased serum phosphorus and was closely associated with necrosis in heart, liver and kidney and haemorrhage in the lung at exposures comparable to the human clinical exposure. In rats, hypertrophy of the physis and increased bone turnover were observed. In rats and dogs given trametinib at or below human clinical exposures, bone marrow necrosis, lymphoid atrophy in thymus and GALT and lymphoid necrosis in lymph nodes, spleen and thymus were observed, which have the potential to impair immune function. In juvenile rats, increased heart weight with no histopathology was observed at 0.35 mg/kg/day (approximately 2 times the human clinical exposure based on AUC).
Trametinib was phototoxic in an in vitro mouse fibroblast 3T3 Neutral Red Uptake (NRU) assay at significantly higher concentrations than clinical exposures (IC50 at 2.92 µg/ml, ≥130 times the human clinical exposure based on Cmax), indicating that there is low risk for phototoxicity to patients taking trametinib.
In a study in dogs in which trametinib and dabrafenib were given in combination for 4 weeks, signs of gastrointestinal toxicity and decreased lymphoid cellularity of the thymus were observed at lower exposures than in dogs given trametinib alone. Otherwise, similar toxicities were observed as in comparable monotherapy studies.
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