Chemical formula: C₂₃H₁₇FN₆O Molecular mass: 412.428 g/mol PubChem compound: 25145656
Capmatinib is an inhibitor of the MET receptor tyrosine kinase. Capmatinib inhibits MET phosphorylation (both autophosphorylation and phosphorylation triggered by the ligand hepatocyte growth factor [HGF]), MET-mediated phosphorylation of downstream signalling proteins, as well as proliferation and survival of MET-dependent cancer cells.
Capmatinib did not prolong the QT interval to any clinically relevant extent following administration of capmatinib at the recommended dose.
In GEOMETRY mono-1, MET exon 14 skipping mutations were determined using a qualitative realtime PCR test (RT-PCR) designed to detect exon 14-deleted MET mRNA derived from formalin-fixed, paraffin-embedded human tissue. The test is indicated as an aid in selecting non-small cell lung cancer (NSCLC) patients whose tumours carry a MET mutation that causes in-frame deletion of the entire exon 14 (141 bases) in mRNA for treatment with capmatinib.
Capmatinib exhibited dose-proportional increases in systemic exposure (AUCinf and Cmax) across the dose range tested (200 to 400 mg twice daily). Steady-state is expected to be achieved after approximately 3 days after oral dosing of capmatinib 400 mg twice daily, with a geometric mean accumulation ratio of 1.39 (coefficient of variation (CV): 42.9%). Inter-individual variability of Cmax and AUCtau was estimated to be 38% and 40%, respectively.
In humans, absorption is rapid after oral administration of capmatinib. Under fasted conditions, peak plasma levels of capmatinib (Cmax) were reached approximately 1 to 2 hours (Tmax) after an oral 400 mg dose of capmatinib tablets in cancer patients. Under fed conditions, Tmax is approximately 4-6 hours. The absorption of capmatinib tablets after oral administration is estimated to be greater than 70%.
Food does not alter capmatinib bioavailability to a clinically meaningful extent. Capmatinib can be administered with or without food. When capmatinib was administered with food in healthy subjects, oral administration of a single 600 mg dose with a high-fat meal increased capmatinib AUCinf by 46% and no change in Cmax compared to when capmatinib was administered under fasted conditions. A low-fat meal in healthy subjects had no clinically meaningful effect on capmatinib exposure. When capmatinib was administered at 400 mg twice daily in cancer patients, exposure (AUC0-12h) was similar after administration of capmatinib with food and under fasted conditions.
Capmatinib is 96% bound to human plasma proteins, independent of concentration. The apparent mean volume of distribution at steady-state (Vss/F) is 164 litres in cancer patients.
The blood-to-plasma ratio was 1.5 (concentration range of 10 to 1000 ng/ml), but decreased at higher concentrations to 0.9 (concentration 10000 ng/ml), indicating a saturation of distribution into red blood cells. Capmatinib crosses the blood-brain barrier.
in vitro and in vivo studies indicated that capmatinib is cleared mainly through metabolism driven by cytochrome P450 (CYP) 3A4 (40-50%) and aldehyde oxidase (40%). The biotransformation of capmatinib occurs essentially by Phase I metabolic reactions including C-hydroxylation, lactam formation, N-oxidation, N-dealkylation, carboxylic acid formation, and combinations thereof. Phase II reactions involve glucuronidation of oxygenated metabolites. The most abundant radioactive component in plasma is unchanged capmatinib (42.9% of radioactivity AUC0-12h). The major circulating metabolite, M16 (CMN288), is pharmacologically inactive and accounts for 21.5% of the radioactivity in plasma AUC0-12h.
The effective elimination half-life (calculated based on geometric mean accumulation ratio) of capmatinib is 6.54 hours. The geometric mean steady-state apparent oral clearance (CLss/F) of capmatinib was 19.8 litres/hour.
Capmatinib is eliminated mainly through metabolism, and subsequent faecal excretion. Following a single oral administration of [14C]-capmatinib capsule to healthy subjects, 78% of the total radioactivity was recovered in the faeces and 22% in the urine. Excretion of unchanged capmatinib in urine is negligible.
No overall differences in the safety or effectiveness were observed between patients aged 65 and 75 years or older and younger patients.
Population pharmacokinetic analysis showed that there is no clinically relevant effect of age, gender, race, or body weight on the systemic exposure of capmatinib.
Based on a population pharmacokinetic analysis that included 207 patients with normal renal function (creatinine clearance [CLcr] ≥90 ml/min), 200 patients with mild renal impairment (CLcr 60 to 89 ml/min), and 94 patients with moderate renal impairment (CLcr 30 to 59 ml/min), mild or moderate renal impairment had no clinically significant effect on the exposure of capmatinib. Capmatinib has not been studied in patients with severe renal impairment (CLcr 15 to 29 ml/min).
A study was conducted in non-cancer subjects with various degrees of hepatic impairment based on Child-Pugh classification using a 200 mg single-dose of capmatinib. The geometric mean systemic exposure (AUCinf) of capmatinib was decreased by approximately 23% and 9% in subjects with mild (N=6) and moderate (N=8) hepatic impairment, respectively, and increased by approximately 24% in subjects with severe (N=6) hepatic impairment compared to subjects with normal (N=9) hepatic function. Mild, moderate or severe hepatic impairment had no clinically significant effect on the exposure of capmatinib.
Capmatinib exposure-response relationships and the time course of the pharmacodynamic response are unknown.
In vitro studies showed that capmatinib is an inhibitor of CYP2C8, CYP2C9 and CYP2C19. Capmatinib also showed weak induction of CYP2B6 and CYP2C9 in cultured human hepatocytes. Simulations using PBPK models predicted that capmatinib given at a dose of 400 mg twice daily is unlikely to cause clinically relevant interaction via CYP2B6, CYP2C8, CYP2C9 or CYP2C19.
Based on in vitro data, capmatinib is a P-gp substrate, but not a BCRP or multidrug resistance-associated (MRP2) substrate. Capmatinib is not a substrate of transporters involved in active hepatic uptake in primary human hepatocytes.
Based on in vitro data, capmatinib and its major metabolite CMN288 showed reversible inhibition of renal transporters MATE1 and MATE2K. Capmatinib may inhibit MATE1 and MATE2K at clinically relevant concentrations.
Based on in vitro data, capmatinib showed reversible inhibition of hepatic uptake transporters OATP1B1, OATP1B3, and OCT1. However, capmatinib is not expected to cause clinically relevant inhibition of OATP1B1, OATP1B3, and OCT1 uptake transporters based on the concentration achieved at the therapeutic dose. Capmatinib is not an inhibitor of renal transporters OAT1 or OAT3. Capmatinib is not a MRP2 inhibitor in vitro.
Signs indicative of CNS toxicity (such as tremors and/or convulsions), and histopathological findings of white matter vacuolation in the thalamus/caudate/putamen regions of the midbrain were observed in rats at doses ≥2.9 exposure multiples of the human clinical exposure based on AUC at the 400 mg twice daily dose. No signs of CNS toxicity or brain abnormalities were observed in cynomolgus monkey studies. The relevance of the CNS findings in rats to humans is unknown.
Capmatinib crossed the blood-brain barrier in rats with a brain-to-blood exposure (AUCinf) ratio of approximately 9%.
A reversible, minimal-to-mild subcapsular neutrophilic infiltration associated with single cell necrosis was seen in the liver of male monkeys treated for 13 weeks at dose levels of ≥4.7 exposure multiples of the human clinical exposure based on AUC at the 400 mg twice daily dose.
Capmatinib is not genotoxic based on a standard battery of in vitro and in vivo tests.
In embryo-foetal development studies in rats and rabbits, capmatinib was teratogenic and foetotoxic at dose levels not eliciting maternal toxicity. In rats, decreased foetal weight and increased incidence of litters and foetuses with limb malformations were observed at the maternal exposure of ≥0.89 exposure multiples of the anticipated clinical exposure (based on the AUC). In rabbits, limb, lung and tongue malformations were seen at the maternal exposure of ≥0.025 exposure multiples of the anticipated clinical exposure.
In vitro and in vivo photosensitisation assays with capmatinib suggested that capmatinib has the potential for photosensitisation.
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