Chemical properties

Afatinib dimaleate is the salt form of Afatinib, a crystalline compound whose structure is shown in Figure 1 below.Afatinib has two basic groups, dimethylamine (pKa 8.2) and quinazoline (pKa 5.0). Afatinib dimaleate is very soluble in water and aqueous buffers with a pH of 1 to 6 (> 50 mg/ mL). The free base is strongly lipophilic (log P = 4.7) but is strongly pH dependent. Afatinib covalently binds to the epidermal growth factor receptor. The molecule is sensitive to the humidity of the drug and the tablet.

Indications

The branded drug ‘Gilotrif’ tablets, developed by Boehringer Ingelheim, are formulated with Afatinib dimaleate as the main ingredient. It is approved by the FDA for the treatment of patients with metastatic non-small cell lung cancer (NSCLC). The disease is associated with non-drug resistant epidermal growth factor receptor (EGFR) mutations. It is also used to treat patients with metastatic squamous NSCLC whose disease has progressed after platinum-based chemotherapy.

Mechanism of action

Afatinib is an orally bioavailable anilinoquinazoline derivative, an inhibitor of the receptor tyrosine kinase (RTK) epidermal growth factor receptor (ErbB; epidermal growth factor receptor) family, with antitumour activity. The mechanism of action is that afatinib works by selectively and irreversibly interacting with epidermal growth factor receptors 1 (ErbB1; epidermal growth factor receptor), 2 (ErbB2; epidermal growth factor receptor HER2), and 4 (ErbB4; epidermal growth factor receptor HER4), as well as with certain epidermal growth factor receptor mutants including those consisting of a deletion mutation in exon 19 of the epidermal growth factor receptor or a deletion mutation in mutants caused by mutations in exon 21 (L858R)) bind and inhibit them. This may inhibit tumour growth and angiogenesis in tumour cells overexpressing these RTKs. In addition, afatinib inhibits the epidermal growth factor receptor T790M gatekeeper mutation that is resistant to treatment with first-generation epidermal growth factor receptor inhibitors. Epidermal growth factor receptor (EGFR), HER2 and HER4 are RTKs belonging to the epidermal growth factor receptor superfamily; they play an important role in tumour cell proliferation and tumour angiogenesis and are overexpressed in many cancer cell types.

Side effects

The most common adverse reactions to Afatinib dimaleate include diarrhoea, rash/acne-like dermatitis, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, pruritus, vomiting, and pruritus. Serious adverse reactions may appear to present with dyspnoea, malaise, hypokalaemia, sepsis, pneumonia, hepatotoxicity and keratitis. Other possible side effects include pancreatitis, Toxic epidermal necrolysis/Stevens Johnson syndrome. Seek medical attention if any of these adverse reactions occur.