Temozolomide–Lenvatinib cocrystal (TMZ-LNV cocrystal)

The Temozolomide–Lenvatinib cocrystal is a pharmaceutical solid-state complex consisting of two active pharmaceutical ingredients (APIs) in a defined stoichiometric ratio within a single crystal lattice. Temozolomide is an imidazotetrazine derivative that functions as an oral alkylating agent, primarily used to treat high-grade gliomas such as glioblastoma multiforme. Lenvatinib is a potent multi-kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFR1–3), fibroblast growth factor receptors (FGFR1–4), and other tyrosine kinases involved in pro-angiogenic and oncogenic pathways. The formation of a cocrystal between these two drugs is intended to optimize their physicochemical properties, such as solubility and dissolution rates, while potentially providing a synergistic therapeutic effect against resistant tumors. By combining DNA-damaging activity with the inhibition of tumor angiogenesis and growth signaling, this entity aims to improve clinical outcomes in oncology by overcoming common resistance mechanisms associated with monotherapy.

Other names

TMZ-LNV cocrystalTemozolomide-Lenvatinib combinationTemozolomide:Lenvatinib (1:1) cocrystal

The cocrystal functions through the dual mechanisms of its constituent drugs. Temozolomide is a prodrug that undergoes spontaneous hydrolysis at physiological pH to the active metabolite MTIC (3-methyl-(triazen-1-yl)imidazole-4-carboxamide), which methylates DNA at the O6 and N7 positions of guanine, leading to DNA mismatch repair failure and subsequent apoptosis (PubChem CID 5394). Lenvatinib acts as a multi-kinase inhibitor that competitively binds to the ATP-binding site of VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET, thereby blocking downstream signaling pathways like PI3K/AKT and MAPK/ERK that drive tumor angiogenesis and cell proliferation (FDA Label; PubChem CID 9823820).