Chemical formula: C₂₉H₂₈N₆O₂ Molecular mass: 492.583 g/mol
Tepotinib is a reversible Type I adenosine triphosphate (ATP)-competitive small molecule inhibitor of MET. Tepotinib blocked MET phosphorylation and MET-dependent downstream signalling such as the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) pathways in a dose-dependent manner. Tepotinib demonstrated pronounced anti-tumour activity in tumours with oncogenic activation of MET, such as METex14 skipping alterations.
A concentration-dependent increase in QTc interval was observed in the concentration-QTc analysis. At the recommended dose, no large mean increases in QTc (i.e. >20 ms) were detected in patients with various solid tumours. The QTc effect of tepotinib at supratherapeutic exposures has not been evaluated.
In clinical studies, identification of METex14 skipping alterations relied on next generation sequencing using RNA or DNA (1 patient) extracted from formalin-fixed paraffin embedded (FFPE) tumour tissue or using circulating cell free DNA from plasma. Additionally, a RNA-based reverse transcriptase polymerase chain reaction-based method specific for detecting METex14 skipping alterations from fresh frozen tissue was available to patients in Japan.
A mean absolute bioavailability of 71.6% was observed for a single 450 mg dose of tepotinib administered in the fed state; the median time to Cmax was 8 hours (range from 6 to 12 hours).
The presence of food (standard high-fat, high-calorie breakfast) increased the AUC of tepotinib by about 1.6-fold and Cmax by 2-fold.
In human plasma, tepotinib is highly protein bound (98%). The mean volume of distribution (Vz) of tepotinib after an intravenous tracer dose (geometric mean and geoCV%) was 574 L (14.4%).
In vitro studies indicate that tepotinib is a substrate for P-glycoprotein (P-gp).
Overall, metabolism is a major route of elimination, but no single metabolic pathway accounted for more than 25% of tepotinib elimination. Only one major circulating plasma metabolite has been identified, MSC2571109A. There is only a minor contribution of the major circulating metabolite to the overall efficacy of tepotinib in humans.
Effects of tepotinib on other transporters: Tepotinib or its major circulating metabolite inhibit P-gp, BCRP, OCT1 and 2 and MATE1 and 2 at clinically relevant concentrations. At clinically relevant concentrations tepotinib presents no risk for organic-anion-transporting polypeptide (OATP) 1B1 and OATP1B3 or organic anion transporter (OAT) 1 and 3.
Effects of tepotinib on UDP-glucuronosyltransferase (UGT): Tepotinib is an inhibitor of UGT1A9 at clinically relevant concentrations, but the clinical relevance is unknown. Tepotinib and its major circulating metabolite are not inhibitors of the other isoforms (UGT1A1/3/4/6 and 2B7/15/17) at clinically relevant concentrations.
Effect of tepotinib on CYP 450 enzymes: At clinically relevant concentrations neither tepotinib nor the major circulating metabolite represent a risk of inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. Tepotinib or its major circulating metabolite do not induce CYP1A2 and 2B6.
After intravenous administration of single doses, a total systemic clearance (geometric mean and geoCV%) of 12.8 L/h was observed.
After a single oral administration of a radiolabelled dose of 450 mg tepotinib, tepotinib was mainly excreted via the faeces (approximately 78% of the dose was recovered in faeces), with urinary excretion being a minor excretion pathway.
Biliary excretion of tepotinib is a major elimination pathway. The unchanged tepotinib represented 45% and 7% of the total radioactive dose in faeces and urine, respectively. The major circulating metabolite accounted for only about 3% of the total radioactive dose in the faeces.
The effective half-life for tepotinib is approximately 32 h. After multiple daily administrations of 450 mg tepotinib, median accumulation was 2.5-fold for Cmax and 3.3-fold for AUC0-24h.
Tepotinib exposure increases approximately dose-proportionally over the clinically relevant dose range up to 450 mg. The pharmacokinetics of tepotinib did not change with respect to time.
A population kinetic analysis did not show any clinically meaningful effect of age (range 18 to 89 years), race, gender or body weight, on the pharmacokinetics of tepotinib. Data on ethnicities other than Caucasian or Asian are limited.
There was no clinically meaningful change in exposure in patients with mild and moderate renal impairment. Patients with severe renal impairment (creatinine clearance less than 30 mL/min) were not included in clinical studies.
Following a single oral dose of 450 mg, tepotinib exposure was similar in healthy subjects and patients with mild hepatic impairment (Child-Pugh Class A), and was slightly lower (13% lower AUC and 29% lower Cmax) in patients with moderate hepatic impairment (Child-Pugh Class B) compared to healthy subjects. Based on unbound tepotinib concentrations, AUC was about 13% and 24% higher in patients with mild and moderate hepatic impairment, respectively, compared to healthy subjects. The pharmacokinetics of tepotinib have not been studied in patients with severe (Child-Pugh Class C) hepatic impairment.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology or repeated dose toxicity.
No mutagenic or genotoxic effects of tepotinib were observed in in vitro and in vivo studies. However, the maximally feasible dose used in the in vivo micronucleus test in rats provided an estimated systemic exposure close to 3-fold lower than the clinical plasma exposure. The major circulating metabolite was shown to be non-mutagenic.
No studies have been performed to evaluate the carcinogenic potential of tepotinib.
In a first oral embryo-foetal development study, pregnant rabbits received doses of 50, 150, and 450 mg tepotinib hydrochloride hydrate per kg per day during organogenesis. The dose of 450 mg per kg (approximately 61% of the human exposure at the recommended dose of tepotinib 450 mg once daily based on AUC) was discontinued due to severe maternal toxic effects. In the 150 mg per kg group (approximately 40% of the human exposure at the 450 mg clinical dose), two animals aborted and one animal died prematurely. Mean foetal body weight was decreased at doses of ≥150 mg per kg per day. A dose-dependent increase of skeletal malformations, including malrotations of fore and/or hind paws with concomitant misshapen scapula and/or malpositioned clavicle and/or calcaneous and/or talus, were observed at 50 mg per kg (approximately 14% of the human exposure at the 450 mg clinical dose) and 150 mg per kg per day.
In the second embryo-foetal development study, pregnant rabbits received oral doses of 0.5, 5, and 25 mg tepotinib hydrochloride hydrate per kg per day during organogenesis. Two malformed foetuses with malrotated hind limbs were observed: one in the 5 mg per kg group (approximately 0.21% of the human exposure at the recommended dose of tepotinib 450 mg once daily based on AUC) and one in the 25 mg per kg group (approximately 1.3% of the human exposure at the 450 mg clinical dose), together with a generally increased incidence of foetuses with hind limb hyperextension.
Fertility studies of tepotinib to evaluate the possible impairment of fertility have not been performed. No morphological changes in male or female reproductive organs were seen in the repeat-dose toxicity studies in rats and dogs, except for reduced secretion in seminal vesicles of male rats in a 4-week repeat-dose toxicity study at 450 mg per kg per day (comparable to human exposure at the 450 mg clinical dose).
Environmental risk assessment studies have shown that tepotinib has the potential to be very persistent and toxic to the environment.
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