Neratinib Maleate

Absorption

Neratinib maleate (NM) is marketed under the brand name “Nerlynx” and has a high oral dose of 290 mg because of its low and variable oral bioavailability (BA) of 11–39%. In clinical settings, NM is administered orally as six mini tablets with a total dose of 290 mg. The oral dose of NM is divided into six mini tablets to facilitate dose titration in patients experiencing dose-dependent gastrointestinal side effects such as severe diarrhea. The oral dose of NM is decreased by reducing one tablet (out of the initial six tablets at the start of therapy) until the patient can cope with gastrointestinal side effects. At less than 120 mg, i.e., three tablets, discontinuation of therapy is recommended. Since NM is recommended as chronic therapy for one year, the dose-dependent side effects make it difficult to continue the medication due to patient discomfort, thereby resulting in noncompliance with the therapy. NM's low and variable oral bioavailability is primarily due to its poor solubility in intestinal pH conditions and extensive CYP3A4-related metabolism in the gut wall during its intestinal absorption process[1].

Description

Neratinib (HKI-272) is a pan-HER inhibitor, this irreversible tyrosine kinase inhibitor binds and inhibits the tyrosine kinase activity of epidermal growth factor receptors, EGFR (or HER1), HER2 and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways.

Chemical Properties

Neratinib maleate (NM) is an off-white to yellow powder with pKas of 7.65 and 4.66. The molecular formula for neratinib maleate is C30H29ClN6O3·C4H4O4, and the molecular weight is 673.11 Daltons. The chemical name is (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate. The solubility of neratinib maleate increases dramatically as neratinib becomes protonated at acidic pH. NM is a highly lipophilic drug with a Log P of 4.7. It exhibits pH-dependent solubility in the pH range of 1.2 to 7.4. It has good solubility under low pH conditions, with a saturation solubility (Cs) of 100 ± 1 and 22 ± 0.5 mg/mL at pH 1.2 and 3.5, respectively. The solubility of NM decreases significantly as the pH increases. The drug is insoluble at pH 6 (Cs = 90 μg/mL) and above.

Uses

Neratinib Maleate is a codrug; used in preparation of heterobifunctional PROTAC compounds as degraders of estrogen receptor.

Uses

A drug used alone or with capecitabine to treat adults with certain types of HER2-positive breast cancer that have already been treated. It is also being studied in the treatment of other types of cancer. Neratinib maleate blocks certain proteins, which may help keep cancer cells from growing and may kill them. It is a type of tyrosine kinase inhibitor.

Biological Activity

Neratinib is a modified form of the discontinued compound pelitinib, and was originally being develoAdditionally, phase II development of oral neratinib as a neoadjuvant therapy for breast cancer, as a second-line therapy for non-small cell lung cancer, and for other solid tumours is also in progress in numerous countries worldwide. ped by Wyeth (later Pfizer). Oral neratinib is awaiting approval as an extended adjuvant therapy for breast cancer in the EU and in the US. Blocking HER2 function by a small molecule kinase inhibitor, such as neratinib, represents an attractive alternate strategy for the growth inhibition of HER2-positive tumours.

Mechanism of action

Neratinib Maleate is the maleate salt form of neratinib, an orally available, quinazoline-based, irreversible inhibitor of both the receptor tyrosine kinases (RTKs) human epidermal growth factor receptor 2 (HER2; ERBB2) and human epidermal growth factor receptor (EGFR), with potential antineoplastic activity. Upon administration, neratinib targets and covalently binds to the cysteine residue in the ATP-binding pockets of both HER2 and EGFR. This inhibits their activity and results in the inhibition of downstream signal transduction events, induces cell cycle arrest, apoptosis and ultimately decreases cellular proliferation in HER2- and EGFR-expressing tumor cells. EGFR and HER2, RTKs that are mutated or overactivated in many tumor cell types, play key roles in tumor cell proliferation and tumor vascularization.

References

[1] Radhika Rajiv Mahajan. “Design and Evaluation of Clove Oil-Based Self-Emulsifying Drug Delivery Systems for Improving the Oral Bioavailability of Neratinib Maleate.” ACS Applied Energy Materials 16 8 (2024).