Tepotinib
Tepotinib Uses, Dosage, Side Effects, Food Interaction and all others data.
Tepotinib is a MET tyrosine kinase inhibitor intended to treat a variety of MET-overexpressing solid tumors. It was originally developed in partnership between EMD Serono and the University of Texas M.D. Anderson Cancer Center in 2009 and has since been investigated in the treatment of neuroblastoma, gastric cancers, non-small cell lung cancer, and hepatocellular carcinoma. MET is a desirable target in the treatment of certain solid tumors as it appears to play a critical role, both directly and indirectly, in the growth and proliferation of tumors in which it is overexpressed and/or mutated.
Tepotinib was first approved in Japan in March 2020 for the treatment of non-small cell lung cancers (NSCLC) with MET alterations, and was subsequently granted accelerated approval by the US FDA in February 2021, under the brand name Tepmetko, for the treatment of adult patients with metastatic NSCLC and MET exon 14 skipping alterations. It is the first oral MET-targeted tyrosine kinase inhibitor to allow for once-daily dosing, an advantage that may aid in easing the pill burden often associated with chemotherapeutic regimens.
Tepotinib is a highly-selective inhibitor of MET kinase activity, with an average IC50 of approximately 1.7 nmol/L. It has a moderate duration of action necessitating once-daily administration.
| Trade Name | Tepotinib |
| Availability | Prescription only |
| Generic | Tepotinib |
| Tepotinib Other Names | Tepotinib |
| Related Drugs | Opdivo, methotrexate, Keytruda, pembrolizumab, cisplatin, Tagrisso, Avastin |
| Weight | 225mg |
| Type | Oral tablet |
| Formula | C29H28N6O2 |
| Weight | Average: 492.583 Monoisotopic: 492.227374166 |
| Protein binding | Tepotinib is approximately 98% protein-bound in plasma, primarily to serum albumin and alpha-1-acid glycoprotein. Plasma protein binding is independent of drug concentration at clinically relevant exposures. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Tepotinib is an oral tyrosine kinase inhibitor targeted against MET for the treatment of metastatic non-small cell lung cancer in patients exhibiting MET exon 14 skipping mutations.
Tepotinib is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) who have mesenchymal-epithelial transition (MET) exon 14 skipping alterations.
Tepotinib is also used to associated treatment for these conditions: Metastatic Non-Small Cell Lung Cancer
How Tepotinib works
Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase found overexpressed and/or mutated in a variety of tumor types, thus making it a desirable target in their treatment. MET plays a critical role in the proliferation, survival, invasion, and mobilization of tumor cells, and aberrant MET activation is thought to contribute to the development of more aggressive cancers with poorer prognoses.
Tepotinib is a kinase inhibitor directed against MET, including variants with exon 14 skipping - it inhibits MET phosphorylation and subsequent downstream signaling pathways in order to inhibit tumor cell proliferation, anchorage-independent growth, and migration of MET-dependent tumor cells. Tepotinib has also been observed to down-regulate the expression of epithelial-mesenchymal transition (EMT) promoting genes (e.g. MMP7, COX-2, WNT1, MUC5B, and c-MYC) and upregulate the expression of EMT-suppressing genes (e.g. MUC5AC, MUC6, GSK3β, and E-cadherin) in c-MET-amplified gastric cancer cells, suggesting that the tumor-suppressing activity of tepotinib is driven, at least in part, by the negative regulation of c-MET-induced EMT. It has also been shown to inhibit melatonin 1B and nischarin at clinically relevant concentrations, though the relevance of this activity in regards to tepotinib's mechanism of action is unclear.
Toxicity
There are no data regarding overdosage of tepotinib. Symptoms of overdose are likely to be consistent with tepotinib's adverse effect profile and may therefore involve significant gastrointestinal symptoms, musculoskeletal pain, and laboratory abnormalities. Treatment of overdose should involve symptomatic and supportive measures. In the event of overdose, dialysis is unlikely to be of benefit given the high degree of plasma protein binding exhibited by tepotinib.
Food Interaction
- Take with food. Co-administration with a meal improves the absorption of tepotinib.
[Moderate] ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of tepotinib.
When tepotinib was administered after a high-fat, high-calorie meal (approximately 800 to 1000 calories; 150 calories from protein, 250 calories from carbohydrate, 500 to 600 calories from fat), tepotinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2-fold and 1.6-fold, respectively, compared to administration under fasted conditions.
MANAGEMENT: Tepotinib should be administered with food at approximately the same time each day.
Tepotinib Disease Interaction
Moderate: ILD/pneumonitis, liver dysfunction, renal dysfunction
Volume of Distribution
The mean apparent volume of distribution is 1,038L.
Elimination Route
The absolute bioavailability of tepotinib following oral administration is approximately 72%. At the recommended dosage of 450mg once daily, the median Tmax is 8 hours and the mean steady-state Cmax and AUC0-24h were 1,291 ng/mL and 27,438 ng·h/mL, respectively.
Co-administration with a high-fat, high-calorie meal increases the AUC and Cmax of tepotinib by approximately 1.6-fold and 2-fold, respectively.
Half Life
Following oral administration, the half-life of tepotinib is approximately 32 hours.
Clearance
The apparent clearance of tepotinib is 23.8 L/h.
Elimination Route
Following oral administration, approximately 85% of the given dose is excreted in the feces with the remainder excreted in the urine. Unchanged parent drug accounts for roughly half of the dose excreted in the feces, with the remainder comprising the demethylated M478 metabolite, a glucuronide metabolite, the racemic M506 metabolite, and some minor oxidative metabolites. Unchanged parent drug also accounts for roughly half of the dose excreted in the urine, with the remainder comprising a glucuronide metabolite and a pair of N-oxide diastereomer metabolites.
Innovators Monograph
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