阿法替尼

Afatinib dimaleate

(Gilotrif®)

阿法替尼

BIBW-2992

Tablet, oral, EQ 20 mg/30 mg/40 mg afatinib

Afatinib is a receptor tyrosine kinase inhibitor which was first approved in 2013 by FDA of US, indicated for the fist-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21(L858R) substitution mutations as detected by an FDA-approved test.

Developed and marketed by Boehringer-Ingelheim.

The human recommended starting dose is 40 mg (EQ afatinib) orally once daily, taken at least 1 hr before a meal or 2 hrs after a meal.

Worldwide Key Approvals Global Sales ($Million) Key Substance Patent Expiration 2013-Jul (US)

2013-Sep (EU) 2014-Jan (JP) Not Available

2018-Jul (US6251912B1)

2021-Dec (EP1345910B1)

2021-Dec (JP3827641B2)

2021-Dec (CN1277822C)

Mechanism of Action

Afatinib covalently bound to the kinase domains of EGFR (ErbB1), HER (ErbB2) and HER4 (ErbB4), and irreversibility inhibited tyrosine kinase autophosphorylation, resulting in down regulation of ErbB signaling.

Target Binding Selectivity In Vitro Efficacy In Vivo Efficacy

EGFR: IC50=0.5 nM.

EGFR L858R/T790M: IC50=10 nM. HER2: IC50=14 nM, HER4: IC50=1 nM. H1666 cells with EGFR: IC50=60 nM.

H3225 with EGFR L858R: IC50=0.7 nM.

H1975 cells with L858R/T790M: IC50=99 nM.

Significantly inhibited tumor growth in H1975

(L858R/T790M) NSCLC xenograft model:

Afatinib: 15 mg/kg/day, T/C% was 18%.

Pharmacokinetics

Parameters Rats Rabbits Minipigs Healthy Humans

In Vivo Dosage (mg/kg)

4

(i.v.)

8

(p.o.)

1.95

(p.o.)

2

(i.v.)

2

(p.o.)

20

(p.o.)

30

(p.o.)

40

(p.o.)

50

(p.o.)

C max (nM) 1620 397 34 1190 29 8 14 24 37

T max (hr) NA 4 1 0.083 4 5 5 5 5 AUC inf (nM·hr) 2920 2600 178 2000 214 189 327 549 724 T1/2 (hr) 5.2 4.5 2.6 13.8 10.8 30.7 32.9 29.6 28.5 CL(/F) (mL/min/kg) 55 108 467 35 NA

1770

mL/min

1530

mL/min

1210

mL/min

1150

mL/min Vd (L/kg) 16 44 110 12 NA 4700 L 4350 L 3110 L 2840 L F (%) - 44.5 NA - 11.2 NA NA NA NA Main component in plasma (%) Parent (59) Parent (36) NA Parent (NA)

Major Metabolites in plasma (%) NA

M2 (27,

inactive)

NA Trace amount (inactive) Excretion by Urine/Feces (%) 6/91 3/94 1/95 NA 2/93 1/85

In Vitro Permeability Papp(A→B)=7.5-12×10-6cm/s in Caco-2 models.

PPB (%Bound) 92.6 NA 92.9 95.0 Metabolic stability in LM NA Low metabolic rate

Drug-Drug Interaction

Substrate Inhibitor Inducer

CYP Enzymes

CYP3A4 (minor)

Weakly inhibited CYP2C9

Not

Other Enzymes

Michael addition (non-enzyme)

Weakly inhibited UGT1A1, 2B7

NA

Transporters

P-gp, BCRP

P-gp and BCRP,OATP-B, OCT3, OCT1

NA

Non-clinical Toxicology

Single Dose Toxicity (MTD) Mice: 300 mg/kg

Rats: 300 mg/kg

Safety

Pharmacology

•hERG potassium current inhibition (IC50=2.4 μM).

•Increased arterial blood and heart rate pressure, prolonged gastric empting

but no effects on respiration rate in telemetered rats.

•Probable phototoxicity: PIF=3.

Repeated Dose Toxicity (NOAEL)Rats: 1.5 mg/kg/day

(0.19 & 0.06× MRHD)

Minipigs: 0.5 mg/kg/day

(0.02 & 0.01× MRHD)

(Male & Female)

Genotoxicity

•Potential mutagenic effects in TA 98 Ames assay at 30 μg/plate but no

clastogenic effect.

Reproductive

Toxicity

•Fertility NOAEL: 6 mg/kg/day in rats.

•Embryonic development: maternal NOAEL: 8 & 5 mg/kg/day (rats & rabbits)

•Postnatal development: NOAEL: 8 mg/kg/day in rats.

•Afatinib can cross placenta (very low concentration in fetal liver) in rats.

•Afatinib was excreted to milk (milk to plasma ratio >100 ) in lactating rats.