Daconib 45 mg (Dacomitinib)

Description

COMPOSITION
DACONIB 15 tablet: Each film coated tablet contains
Dacomitinib Monohydrate INN equivalent to Dacomitinib
15 mg.
DACONIB 45 tablet: Each film coated tablet contains
Dacomitinib Monohydrate INN equivalent to Dacomitinib
45 mg.
PHARMACOLOGY
Mechanism of Action
Dacomitinib is an irreversible inhibitor of the kinase activity
of the human EGFR family (EGFR/HER1, HER2, and HER4)
and certain EGFR activating mutations (exon 19 deletion or
the exon 21 L858R substitution mutation). In vitro
Dacomitinib also inhibited the activity of DDR1, EPHA6,
LCK, DDR2, and MNK1 at clinically relevant concentrations.
Dacomitinib demonstrated dose-dependent inhibition of
EGFR and HER2 autophosphorylation and tumor growth in
mice bearing subcutaneously implanted human tumor
xenografts driven by HER family targets including mutated
EGFR. Dacomitinib also exhibited antitumor activity in
orally-dosed mice bearing intracranial human tumor
xenografts driven by EGFR amplifications.
Pharmacokinetic properties
The maximum Dacomitinib plasma concentration (Cmax)
and AUC at steady state increased proportionally over the
dose range of Dacomitinib 2 mg to 60 mg orally once daily
(0.04 to 1.3 times the recommended dose) across
Dacomitinib studies in patients with cancer. At a dose of 45
mg orally once daily, the geometric mean [coefficient of
variation (CV%)] Cmax was 108 ng/mL (35%) and the
AUC0-24h was 2213 ng•h/mL (35%) at steady state in a
dose-finding clinical study conducted in patients with solid
tumors. Steady state was achieved within 14 days following
repeated dosing and the estimated geometric mean (CV%)
accumulation ratio was 5.7 (28%) based on AUC.
Absorption
The mean absolute bioavailability of Dacomitinib is 80%
after oral administration. The median Dacomitinib time to
reach maximum concentration (T max) occurred at approxi-
mately 6.0 hours (range 2.0 to 24 hours) after a single oral
dose of Dacomitinib 45 mg in patients with cancer.
Effect of food
Administration of Dacomitinib with a high-fat, high-calorie
meal (approximately 800 to 1000 calories with 150, 250,
and 500 to 600 calories from protein, carbohydrate and fat,
respectively) had no clinically meaningful effect on
Dacomitinib pharmacokinetics.
Distribution
The geometric mean (CV%) volume of distribution of
Dacomitinib (Vss) was 1889 L (18%). In vitro binding of
Dacomitinib to human plasma proteins is approximately
98% and is independent of drug concentrations from 250
ng/mL to 1000 ng/mL.
Elimination
Following a single 45 mg oral dose of Dacomitinib in
patients with cancer, the mean (CV%) plasma half-life of
Dacomitinib was 70 hours (21%), and the geometric mean
(CV%) apparent plasma clearance of Dacomitinib was 24.9
L/h (36%).