Singapore Drugs Database

Indication

Afatinib is a kinase inhibitor indicated as monotherapy [L2937] for the first-line [FDA Label] treatment of (a) Epidermal Growth Factor Receptor (EGFR) TKI (tyrosine kinase inhibitor)-naive adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have non-resistant EGFR mutations as detected by an FDA-approved test [FDA Label], and (b) adult patients with locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy [FDA Label, L2937]. Recently, as of January 2018, the US FDA approved a supplemental New Drug Application for Boehringer Ingelheim's Gilotrif (afatinib) for the first line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test [L2939]. The new label includes data on three additional EGFR mutations: L861Q, G719X and S768I [L2939].

Mechanism of Action

Afatinib is a potent and selective, irreversible ErbB family blocker [L2937]. Afatinib covalently binds to and irreversibly blocks signaling from all homo and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4 [L2937]. In particular, afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling [FDA Label]. Certain mutations in EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC [FDA Label]. Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods [FDA Label]. The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions [FDA Label]. Moreover, afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved in patients [FDA Label]. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2 [FDA Label].

Pharmacokinetics

Absorption

Following oral administration, time to peak plasma concentration (Tmax) is 2 to 5 hours [FDA Label]. Maximum concentration (Cmax) and area under the concentration-time curve from time zero to infinity (AUC0-∞) values increased slightly more than dose proportional in the range of 20 to 50 mg [FDA Label]. The geometric mean relative bioavailability of 20 mg tablets was 92% as compared to an oral solution [FDA Label]. Additionally, systemic exposure to afatinib is decreased by 50% (Cmax) and 39% (AUC0-∞), when administered with a high-fat meal compared to administration in the fasted state [L2937]. Based on population pharmacokinetic data derived from clinical trials in various tumor types, an average decrease of 26% in AUCss was observed when food was consumed within 3 hours before or 1 hour after taking afatinib [L2937].

Distribution

The volume of distribution of afatinib recorded in healthy male volunteers is documented as 4500 L [A33298]. Such a high volume of distribution in plasma suggests a potentially high tissue distribution [A33298].

Metabolism

Enzyme-catalyzed metabolic reactions play a negligible role for afatinib in vivo [L2937]. Covalent adducts to proteins were the major circulating metabolites of afatinib [L2937].

Elimination

Clearance

The apparent total body clearance of afatinib as recorded in healthy male volunteers is documented as being a high geometric mean of 1530 mL/min [A33298].

Toxicity

Most common adverse reactions (≥20%) are diarrhea, rash/dermatitis, acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus [FDA Label]. Conversely, overdose in 2 healthy adolescents involving the ingestion of 360 mg each of afatinib (as part of a mixed drug ingestion) was associated with adverse events of nausea, vomiting, asthenia, dizziness, headache, abdominal pain and elevated amylase (

Active Ingredient/Synonyms

Afatinibum | Afatinib |