afatinib

Action and Spectrum

Actions and Spectrum: 

Mechanism of Action:  

• afatinib works by irreversibly binding and inhibiting the activity of multiple members of the epidermal growth factor receptor (EGFR) family, including EGFR (ErbB1), human epidermal growth factor receptor 2 (HER2 or ErbB2), and ErbB4. These receptors play a crucial role in the signaling pathways involved in cell growth, proliferation, and survival. 
• By inhibiting EGFR family receptors, afatinib prevents the activation of downstream signaling pathways, such as the RAS/RAF/MEK/ERK pathway and the PI3K/AKT/mTOR pathway. These pathways are often dysregulated in cancer cells, leading to uncontrolled cell growth and tumor progression. afatinib helps inhibit cancer cells’ growth and survival by blocking these signaling pathways. 

Spectrum of Activity:  

• afatinib is primarily indicated for treating NSCLC, particularly in patients with tumors with specific mutations in the EGFR gene. These mutations include exon 19 deletions or the L858R substitution mutation in exon 21. These mutations lead to the constitutive activation of EGFR signaling and are found in a subset of NSCLC patients. 
• afatinib effectively inhibits the growth of cancer cells harboring these EGFR mutations, which are commonly associated with increased sensitivity to EGFR inhibitors. It has shown clinical benefit in treatment-naive patients and those who have progressed after receiving first-line EGFR TKIs. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Dermatitis acneiform (70-90%) 

Paronychia (11-58%) 

Dry skin (31%) 

Decreased appetite (25%) 

Nausea (21%) 

Decreased weight (17%) 

Cystitis (13%) 

Cheilitis (12%) 

Diarrhea (75-96%) 

Stomatitis (30-71%) 

Increased ALT (10-54%) 

Decreased potassium (11-30%) 

Pruritus (21%) 

Epistaxis (17%) 

Vomiting (13%) 

Decreased WBC (12%) 

Rhinorrhea (11%)  

1-10% 

(Grade 3 or 4) 

Increased ALT (1-2%) 

Vomiting (1%) 

Cystitis (1%) 

Nausea (2%) 

Decreased WBC (1%) 

Increased bilirubin (1%) 

Decreased weight (1%) 

<1% 

Keratitis 

Black Box Warning

Black box warning: 

None 

Contraindication / Caution

Contraindications/caution: 

Contraindications: 

None 

Caution: 

• Interstitial Lung Disease (ILD): afatinib has been associated with developing ILD, a potentially severe and life-threatening lung condition.  
• Diarrhea: Diarrhea is a common side effect of afatinib treatment. It can range from mild to severe, leading to dehydration and electrolyte imbalances.  
• Skin and Nail Toxicities: afatinib can cause skin and nail toxicities, such as rash, acneiform dermatitis, dry skin, and paronychia (inflammation of the nail bed). 
• Hepatic Toxicity: afatinib may lead to liver function abnormalities, including elevated liver enzymes.

Pregnancy / Lactation

Pregnancy consideration: afatinib can cause fetal harm and is not recommended during pregnancy.  

Lactation: Excretion of the drug in human breast milk is unknown, but advised to avoid breastfeeding while taking afatinib due to the potential risk to the infant. 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

• afatinib irreversibly binds to the tyrosine kinase domains of EGFR (ErbB1), human epidermal growth factor receptor 2 (HER2 or ErbB2), and ErbB4. By binding to these receptors, afatinib inhibits their phosphorylation, which prevents downstream signaling pathways from being activated. 
• The EGFR family of receptors plays a crucial role in regulating cell growth, proliferation, and survival. Mutations in EGFR are commonly found in certain types of cancers, particularly non-small cell lung cancer (NSCLC). afatinib effectively targets and inhibits cancer cells with specific EGFR mutations, such as exon 19 deletions or the L858R substitution mutation in exon 21. 

Pharmacodynamics: 

• afatinib inhibits EGFR and other ErbB family receptors’ autophosphorylation by irreversibly binding to their tyrosine kinase domains. This inhibition prevents the activation of downstream signaling pathways, including the RAS/RAF/MEK/ERK pathway and the PI3K/AKT/mTOR pathway. 
• These signaling pathways are frequently dysregulated in cancer cells, leading to uncontrolled cell growth and survival. By inhibiting these pathways, afatinib helps to suppress cancer cell proliferation and promote cell death. 

Pharmacokinetics: 

Absorption 

afatinib has a bioavailability of approximately 92%, indicating that a significant portion of the drug is absorbed into the systemic circulation. The peak plasma concentration of afatinib is reached within 2 to 5 hours after oral administration. Taking afatinib with a high-fat meal decreases the maximum plasma concentration (Cmax) by 50% and the area under the plasma concentration-time curve (AUC) by 39% compared to the fasted condition. Therefore, it is recommended to take afatinib on an empty stomach. 

Distribution 

afatinib is highly protein-bound, with approximately 95% bound to plasma proteins. It primarily binds to albumin and alpha-1-acid glycoprotein. 

Metabolism 

The primary circulating metabolites of afatinib are covalent adducts formed by binding to proteins. The extent of enzymatic metabolism of afatinib is minimal. 

Elimination and Excretion 

The elimination half-life of afatinib is approximately 37 hours, indicating a relatively long duration of action. afatinib is primarily eliminated through feces (85% of the administered dose) and, to a lesser extent, through urine (4% of the administered dose). 

Adminstartion

Administration: 

Oral administration 

Oral administration should occur one to two hours before or after a meal.  

If there is less than 12 hours before your next scheduled dosage, skip the missed dose. 

Storage 

Keep at room temperature (about 77°F), ideally between 15 and 30 degrees (59 and 86°F).  

Dispense back into the original packaging to avoid light and moisture damage. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: afatinib 

Why do we use afatinib? 

afatinib is a medication used to treat specific types of cancer, particularly non-small cell lung cancer (NSCLC), with specific genetic mutations. Here are the primary uses of afatinib: 

• NSCLC with EGFR Mutations: afatinib is primarily used to treat NSCLC in patients with specific epidermal growth factor receptor (EGFR) gene mutations. These mutations include exon 19 deletions or the L858R substitution mutation in exon 21. afatinib has shown efficacy in both treatment-naive patients and those who have progressed after receiving first-line EGFR tyrosine kinase inhibitors (TKIs). 
• Advanced or Metastatic NSCLC with HER2 Mutations: afatinib is also approved for treating NSCLC in patients with tumors with HER2 (human epidermal growth factor receptor 2) mutations. HER2 mutations are less common than EGFR mutations but can be present in a subset of NSCLC patients.