COMPOSITION
Capmaxen tablet: Each film coated tablet contains Capmatinib
Hydrochloride INN equivalent to Capmatinib 200 mg.
PHARMACOLOGY
Mechanism of Action:
Capmatinib is a kinase inhibitor that targets MET, including the
mutant variant produced by exon 14 skipping. MET exon 14 skipping
results in a protein with a missing regulatory domain that reduces its
negative regulation leading to increased downstream MET signaling.
Capmatinib inhibited cancer cell growth driven by a mutant MET
variant lacking exon 14 at clinically achievable concentrations and
demonstrated anti-tumor activity in murine tumor xenograft models
derived from human lung tumors with either a mutation leading to
MET exon 14 skipping or MET amplification. Capmatinib inhibited the
phosphorylation of MET triggered by binding of hepatocyte growth
factor or by MET amplification, as well as MET mediated
phosphorylation of downstream signaling proteins and proliferation
and survival of MET-dependent cancer cells.
Pharmacokinetic properties
Capmatinib exposure (AUC0-12h and Cmax) increased
approximately proportionally over a dose range of 200 mg (0.5 times
the recommended dosage) to 400 mg. Capmatinib reached
steady-state by day 3 following twice daily dosing, with a mean (%
coefficient of variation [%CV]) accumulation ratio of 1.5 (41%).
Absorption
After administration of Capmatinib 400 mg orally in patients with
cancer, Capmatinib peak plasma concentrations (Cmax) were
reached in approximately 1 to 2 hours (Tmax). The absorption of
Capmatinib after oral administration is estimated to be greater than
70%.
Effect of food
A high-fat meal (containing approximately 1000 calories and 50% fat)
in healthy subjects increased capmatinib AUC0-INF by 46% with no
change in Cmax compared to under fasted conditions. A low-fat meal
(containing approximately 300 calories and 20% fat) in healthy
subjects had no clinically meaningful effect on capmatinib exposure.
When Capmatinib was administered at 400 mg orally twice daily in
cancer patients, exposure (AUC0-12h) was similar after administra-
tion of Capmatinib with food and under fasted conditions.
Distribution
Capmatinib plasma protein binding is 96%, independent of
Capmatinib concentration. The apparent mean volume of distribution
at steady-state is 164 L.
The blood-to-plasma ratio was 1.5, but decreased at higher
concentrations to 0.9
Elimination
The effective elimination half-life of Capmatinib is 6.5 hours. The
mean (%CV) steady-state apparent clearance of Capmatinib is 24
L/hr (82%)