Selective Tyrosine Kinase Inhibitors: Imatinib and Osimertinib

Mechanism

Pharmacological Class and Group

Orally targeted synthetic small molecules, reversible and irreversible inhibitors of membrane or cytoplasmic kinases.

Mechanism of Action

• Imatinib: It is a selective inhibitor of the ATP-binding cleft of the tyrosine kinase BCR-ABL (the chimeric protein synthesized by the translocation of the Philadelphia t(9;22) chromosome). By blocking the ATP pocket, it prevents the autophosphorylation of the kinase, silencing the mitogenic cascades that promote uncontrolled myeloid proliferation of leukemia. It also acts as an inhibitor of the membrane receptor tyrosine kinase KIT (CD117) and PDGFR.
• Osimertinib: It is a third-generation tyrosine kinase inhibitor that binds covalently and irreversibly to the Cys797 residue in the kinase domain of mutated EGFR receptors. It is designed to selectively block both the primary sensitization mutations (L858R and axon 19 deletion) and the acquired secondary gatekeeper resistance mutation T790M, largely sparing wild-type EGFR to reduce skin and colon toxicity.

Blocking the T790M Mutation by Osimertinib

The acquired resistance mutation T790M consists of the substitution of a threonine for a methionine at position 790 in the ATP-binding pocket domain of EGFR. This mutation generates a steric hindrance that increases the affinity of the kinase for ATP, competitively displacing the first generation inhibitors (Erlotinib, Gefitinib):

EGFR-T790M Extreme Affinity for ATP 1st Gene ITK Failure Tumor Resistance

Osimertinib circumvents this resistance by forming an irreversible covalent bond with cysteine residue 797 of the kinase, which persistently silences the receptor signal independently of competing ATP, inducing apoptosis in the mutated tumor cells.

Pharmacokinetics

High Resolution Pharmacokinetics

• Oral Absorption and Bioavailability: Excellent rapid oral absorption, with a bioavailability of 98% for imatinib (taken with food to reduce direct gastric irritation). Osimertinib has slow absorption with bioavailability greater than 70%, independent of gastric pH.
• Metabolism: Extensive phase I hepatic metabolism mediated predominantly by the cytochrome P450 isoenzyme CYP3A4 for both drugs. Imatinib generates the N-demethylated active circulating metabolite; osimertinib is biotransformed to the active metabolites AZ5104 and AZ7550.
• Elimination: Predominant hepatobiliary clearance, with more than 70-80% of the doses excreted in the feces as active and inactive metabolites.
• Half-life (t_1/2): The elimination half-life is approximately 18 hours for imatinib, facilitating a daily oral dose; that of osimertinib is prolonged, approximately 48 to 55 hours.

Indicators and dose

Clinical Indications and Frequent Regimens

• Imatinib: Philadelphia positive (Ph+) Chronic Myeloid Leukemia (CML) in chronic, accelerated phase or blast crisis; Gastrointestinal Stromal Tumors (GIST) that express positive KIT (CD117) receptors metastatic or as a surgical adjuvant.
• Osimertinib: Metastatic or adjuvant non-small cell lung cancer with active EGFR priming mutations detected, or with acquired T790M mutation positive after previous TKI failure.

Dosage and Clinical Adjustment

• Oral imatinib: 400 - 600 mg orally once daily with food and a large glass of water.
• Oral osimertinib: 80 mg orally once a day continuously, with or without food.
• Clinical Settings: For imatinib, if there is hematological toxicity (platelets < 50,000/mm³ or neutrophils < 1000/mm³), suspend until recovery and resume at doses of 300 - 400 mg/day. For osimertinib, if interstitial pneumonitis is suspected, discontinue immediately and permanently; If there is QTc prolongation > 500 ms, interrupt until recovery and readjust the dose to 40 mg/day.

Security

Absolute and Relative Contraindications

Contraindications of Imatinib

• Hypersensitivity to the active ingredient.
• Moderate to severe renal dysfunction with a decompensated course.
• Pregnancy confirmed.

Contraindications of Osimertinib

• History of diffuse interstitial pneumonitis or drug-induced pulmonary fibrosis.
• Concomitant use of strong cytochrome CYP3A4 inducers.
• Pregnancy and breastfeeding.

Adverse Effects (ADR) and Specific Toxicity

• Imatinib: Periorbital edema and mild recurrent superficial water retention (due to alteration of the PDGFR receptor in fibroblasts of the dermis), myalgia and benign painful muscle spasms, mild-moderate diarrhea.
• Osimertinib: Mild diarrhea, papulopustular rash of lower intensity compared to first-generation TKI, brittle nail (diffuse paronychia), Interstitial Lung Disease (ILD) with a life-threatening course (manifested by dry cough, dyspnea on exertion and ground-glass opacities on CT), prolongation of the QTc interval cardiac.