Afatinib Dimaleate
Afatinib dimaleate was first approved by the U.S. Food and Drug Administration (FDA) on July 12, 2013, then approved by European Medicine Agency (EMA) on Sept 25, 2013, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Jan 17, 2014. It was developed and marketed as Gilotrif® by Boehringer-Ingelheim Corporation.
Afatinib dimaleate is an irreversible inhibitor of the ErbB family of receptor tyrosine kinases (TKI). It covalently binds to and blocks signalling from all homo-and heterodimers formed by the ErbB family members EGFR (ErbB1), HER 2 (ErbB2), ErbB3 and ErbB4. Aberrant ErbB signalling triggered by receptor mutations, and/or amplification, and/or receptor ligand over-expression contributes to the malignant phenotype. It is indicated for the first-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.
Gilotrif® is available as film-coated, tablet for oral use, containing 20, 30 or 40 mg of free Afatinib. The recommended dose is 40 mg orally, once daily (at least 1 hour before or 2 hours after a meal).
Update Date：2016-04-22
- Drug Name：
- Afatinib Dimaleate
- Research Code：
- BIBW-2992; Tovok
- Trade Name：
- Gilotrif® / Giotrif®
- MOA：
- Kinase inhibitor
- Indication：
- Non small cell lung cancer (NSCLC)
- Status：
- Approved
- Company：
- Boehringer Ingelheim (Originator)
- Sales：
- ATC Code：
- L01XE13
Update Date：2016-03-03
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-07-12 | Marketing approval | Gilotrif | Non small cell lung cancer (NSCLC) | Tablet, Film coated | Eq. 20 mg/30 mg/40 mg Afatinib | Boehringer Ingelheim | Orphan |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-09-25 | Marketing approval | Giotrif | Non small cell lung cancer (NSCLC) | Tablet, Film coated | Eq. 20 mg/30 mg/40 mg/50 mg Afatinib | Boehringer Ingelheim |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2014-01-17 | Marketing approval | Giotrif | Non small cell lung cancer (NSCLC) | Tablet, Film coated | Eq. 20 mg/30 mg/40 mg/50 mg Afatinib | Boehringer Ingelheim |
Update Date：2015-08-27
|
Molecular Weight | 718.1 | ||||||||||||
| Formula | C24H25ClFN5O3•2C4H4O4 | |||||||||||||
| CAS No. |
850140-72-6 (Afatinib); 850140-73-7 (Afatinib Dimaleate); |
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| Chemical Name | (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[(3S)-oxolan-3-yloxy]quinazolin-6-yl}-4-(dimethylamino)but-2-enamide, (2Z)-2-butenedioate (1:2) | |||||||||||||
| Afatinib （Free Acid/Base）Parameters： | ||||||||||||||
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| *：Calculated by ACD/Labs software V11.02. | ||||||||||||||
Update Date：2015-08-31
Update Date：2016-05-11
Update Date：2016-06-07
Mechanism of Action
Afatinib covalently bound to the kinase domains of EGFR, and irreversibly inhibited the tyrosine kinase autophosphorylation HER1 (ErbB1, IC50 = 0.5 nM), HER2 (ErbB2, IC50 = 14 nM) and HER4 (ErbB4, IC50 = 1 nM), resulting in down regulation of ErbB signaling.
Afatinib inhibited autophosphorylation and proliferation of multiple cell lines with wild type EGFR, constitutively active HER2, and EGFR exon 19 deletion mutations or exon 21 L858R mutations, including the L858R/T790M double mutation.
Afatinib showed a minimal off-target effect.
In Vitro Efficacy
Afatinib inhibited proliferation of multiple cell lines.
● Cell lines with constitutively active HER2 or wild type EGFR, IC50 = 12-60 nM.
● Cell lines with EGFR bearing exon 19 deletion mutations, IC50 = 0.7-4 nM.
● NCI-H1975 with L858R/T790M double mutant EGFR, IC50 = 99 nM.
In Vivo Efficacy
Xenograft models which derived from multiple wild type EGFR- or HER2-overexpressing tumor cell lines in nude mice:
● In A431 (i.e. epidermoid carcinoma) model: Significant tumor growth inhibition and tumor regression at 20 mg/kg/day
● In SKOV-3 (ovarian carcinoma) model: Significant efficacy at 15 mg/kg/day
● In NCI-N87 (gastric carcinoma) model: Significant efficacy at 20 mg/kg/day
● In NCI-H1975 (NSCLC with EGFR L858R/T790M double mutation) model: Significant efficacy at 15 mg/kg/day
Update Date：2016-06-07
Absorption of Afatinib
Exhibited a non-linear pharmacokinetics in humans following oral dosing. The increases in Cmax and AUC appeared to be dose-proportional in the dose range of 20 to 50 mg afatinib.
Had a moderate oral bioavailability in rats (44.5%) and low in minipigs (11.2%).
Was absorbed slowly (Tmax = 4-5 h) in rats, minipigs and humans but rapidly in rabbits (Tmax = 1 h).
Showed a half-life of 29.6 h in humans, longer than those in rats (4.54 h), rabbits (2.6 h) and minipigs (10.8 h), after oral administration.
Had a high clearance in rats (55.3 mL/min/kg) and minipigs (35.4 mL/min/kg), compared to liver blood flow, after intravenous administration. The CL/F was 1210 mL/min in humans after oral administration.
Exhibited an extensive distribution or concentrated in tissues in rats, rabbits and minipigs, with apparent volume of distribution at 43.6, 110, 12.4 L/kg, respectively. The apparent volume of distribution in humans was 2800-4700 L after oral administration.
Showed a moderate to high permeability, with a Papp(A→B) of (7.5-12) × 10-6 cm/s in Caco-2 cell monolayer model.
Distribution of Afatinib
Exhibited high plasma protein binding in humans (95.0%), rats (92.6%), mice (94.3%) and minipigs (92.9%).
Has a Cc:Cp ratio of 2.21 in humans, suggesting readily penetration into red blood cells. Note that afatinib was mainly bound to hemoglobin in humans.
Albino and pigmented male rats by a single intravenous administration:
● The drug was rapidly and well distributed into most tissues except the central nervous system since little crossed blood-brain barrier.
● Relatively higher concentration levels were observed in kidneys, adrenal, brown fat, spleen, pituitary, and accessory sex organs of the male, compared to other organs. It was similar between pigmented and albino rats.
● However, in pigmented rats, the concentration of afatinib in the retina of the eye was very high and constant over the investigation period, indicating melanin binding.
● Some accumulation was observed in the liver and kidneys, adrenal, pituitary as well as spleen.
Minipigs following a single oral administration:
● The exposure was wider spread in minipigs.
● The majority of the dose was recovered from the liver and spleen.
● Meanwhile, the autoradiography of the eyes demonstrated afatinib was bound to melanin.
Metabolism of Afatinib
The major metabolites were produced by Michael addition (non-enzymatic), with minor catalyzed by CYP450 enzymes. The metabolite M10 (N-demethylation) catalyzed by CYP3A4 was in trace amount.
Overall, the parent drug represented the most abundant component, with covalent adducts to endogenous proteins as the major metabolite in human plasma. Meanwhile, a few metabolites of afatinib were detected in trace amount in human plasma.
All the metabolites found in humans could be found in other species.
Excretion of Afatinib
Was predominantly eliminated in feces of humans and tested animals, with the parent drug as the most significant component in mouse, rat, rabbit, minipig and human feces.
Approximately 62.3% of the excreted [14C]radioactivity was afatinib, followed by 4.3% as M4, 2.7% as M13 and 0.46% as M2 in human urine after oral administration.
Drug-Drug interaction
Was a weak inhibitor of CYP2C9 (IC50 = 79.3 μM), UGT1A1 (IC50 = 24.2 μM) and UGT2B7 (IC50 = 73.7 μM).
Had no induction of CYP450 (CYP3A4, 2D6, 1A2, 2C19, 2B6, 2C8, 2E1 and 4A11).
Was a substrate of P-gp and BCRP, and had inhibition for P-gp and BCRP.
Was not a substrate of OATP2, OATP8, OATP-B, OAT1, OAT3, OCT1, OCT2, OCT3, and had inhibition for OATP-B (IC50 = 6.05 μM), OCT3 (IC50 = 11.8 μM) and OCT1 (IC50 = 20 μM).
Update Date：2016-06-07
Single-Dose Toxicity
Single-dose oral administration of afatinib in different species:
● Mouse and rat MTD: 300 mg/kg
● Main finding was GI tract toxicity
Repeated-Dose Toxicity
Repeated-dose oral administration of afatinib in different species from 2 to 52 weeks:
● For rats: The NOAEL was 1.5 mg/kg/day (0.19 × and 0.06 × MRHD for males and females, respectively), determined by 26-week study, and the main toxicities were skin lesion, GI tract and kidneys toxicity.
● For Göettingen Minipigs: The NOAEL was 0.5 mg/kg/day (0.02 × and 0.01 × MRHD for males and females, respectively), determined by 52-week study, and the main toxicities were skin lesion, corneal eyes, GI tract and kidneys toxicity.
Safety Pharmacology
Modified IRWIN test in mice: No effects on general behavior or motility.
Afatinib prolonged gastric empting and increased serum and liver enzymes in rats following single-dose administration.
The IC50 of afatinib in the hERG potassium current was 2.4 μM, suggesting low potential for QTc prolongation at clinically relevant concentrations.
In telemetered rats, afatinib (p.o.) increased arterial blood pressure and heart rate at 100 mg/kg. However, no effects were noted on respiration rate and tidal volume.
In domestic pigs, afatinib (i.v.) decreased LV dP/dt-max at 10 and 30 mg/kg, suggesting weakened contractility.
Photo irritation factor (PIF) = 3, which was classified as probable phototoxicity.
Genotoxicity
Both in vitro and in vivo assays were employed to determinate genotoxic potential.
Afatinib demonstrated mutagenic potential at 30 μg/plate in TA 98 in the Ames assay while it was negative in all other tests.
Reproductive and Developmental Toxicity
Fertility toxicity: The NOAEL was 6 mg/kg/day for both male and female rats.
Fetal embryonic developmental toxicity: The NOAEL was 8 and 2.5 mg/kg/day for maternal rats and rabbits, respectively.
Postnatal developmental toxicity: The NOAEL was 8 mg/kg/day.
Milk excretion of afatinib was also found in lactating rats.
No relevant levels of [14C]afatinib were found in embryos and fetuses except very low concentrations in fetal liver.
