Selpercatinib

525.6

525.24883788

207-854-9

CEGM9YBNGD

C134987

White to off-white

L01EX22

1.36±0.1 g/cm3(Predicted)

<1 mg/mL

14.00±0.29(Predicted)

Store at -20°C

Store at -20°C

|Danger|H341 (50%): Suspected of causing genetic defects [Warning Germ cell mutagenicity]|P201, P202, P260, P264, P270, P281, P308+P313, P309+P311, P314, P405, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Toxicity information regarding selpercatinib is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as hepatotoxicity, hypertension, prolonged QT interval, and hemorrhaging. Symptomatic and supportive measures are recommended.

Selpercatinib displays 97% _in vitro_ protein binding independent of concentration and a blood-plasma concentration ratio of 0.7.

Selpercatinib is indicated for the treatment of _RET_ fusion-positive non-small cell lung cancer in adult patients. Selpercatinib is also indicated for the systemic treatment of advanced or metastatic _RET_-mutant medullary thyroid cancer and for the systemic treatment of _RET_ fusion-positive radioactive iodine-refractory thyroid cancer in both adult and pediatric patients aged 12 and over. Selpercatinib is currently approved for these indications under an accelerated approval scheme and continued approval may be contingent on future confirmatory trials.|FDA Label|Treatment of all conditions included in the category of malignant neoplasms (except haematopoietic and lymphoid tissue neoplasms)|Retsevmo as monotherapy is indicated for the treatment of adults with:advanced RET fusion-positive non-small cell lung cancer (NSCLC) who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapyadvanced RET fusion-positive thyroid cancer who require systemic therapy following prior treatment with sorafenib and/or lenvatinibRetsevmo as monotherapy is indicated for the treatment of adults and adolescents 12 years and older with advanced RET-mutant medullary thyroid cancer (MTC) who require systemic therapy following prior treatment with cabozantinib and/or vandetanib.|Drug: Selpercatinib

Selpercatinib exerts anti-tumour activity in specific cancers through inhibition of mutated forms of RET tyrosine kinases. Due to its increased specificity for RET over other tyrosine kinases, selpercatinib is thought to have an improved safety profile compared to other multi-kinase inhibitors. Despite this, selpercatinib treatment is associated with hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, risk of impaired wound healing, and embryo-fetal toxicity; some patients may also exhibit hypersensitivity to selpercatinib.

In patients with locally advanced or metastatic solid tumours receiving 160 mg of selpercatinib twice daily, steady-state was achieved after approximately 7 days, with a C_max of 2,980 (CV 53%) and AUC_0-24h of 51,600 (CV 58%). The absolute bioavailability is between 60 and 82% (mean 73%), and the median t_max is two hours. Food has no apparent effect on the AUC or C_max of selpercatinib. Patients with hepatic impairment display a concomitant increase in AUC_0-INF for mild (7%), moderate (32%), and severe (77%) impairment.|Selpercatinib administered as a single 160 mg dose in healthy individuals was primarily recovered in feces (69%, 14% unchanged) and urine (24%, 12% unchanged).|Selpercatinib has an apparent volume of distribution of 191 L; the volume of distribution increases with increasing body weight.|Selpercatinib has an apparent clearance of 6L/h; the clearance increases with increasing body weight.

Selpercatinib is predominantly metabolized in the liver by CYP3A4.

Selpercatinib has a half-life of 32 hours in healthy individuals.

Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase containing extracellular, transmembrane, and intracellular domains whose activity is required for normal kidney and nervous system development. Constitutive RET activation is primarily achieved through chromosomal rearrangements producing 5' fusions of dimerizable domains to the 3' _RET_ tyrosine kinase domain, such as _KIF5B-RET_ and _CCDC6-RET_, resulting in constitutive dimerization and subsequent autophosphorylation. Constitutive activation leads to increased downstream signalling and is associated with tumour invasion, migration, and proliferation. Selpercatinib is a direct RET kinase inhibitor, exhibiting IC₅₀ values between 0.92 and 67.8 nM depending on the exact _RET_ genotype. Information based on natural as well as induced resistance mutations and molecular modelling suggests that selpercatinib directly inhibits RET autophosphorylation by competing with ATP for binding. Various single amino acid mutations at position 810 inhibit selpercatinib binding without significantly altering ATP binding, potentially leading to treatment failures. Selpercatinib is also reported to inhibit other tyrosine kinase receptors, including VEGFR1, VEGFR3, FGFR1, FGFR2, and FGFR3, at clinically relevant concentrations. The significance of these effects is not well studied.

6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo(3.1.1)heptan-3-yl)pyridin-3-yl)pyrazolo(1,5-a)pyridine-3-carbonitrile

Human Drugs -> EU pediatric investigation plans|Human drugs -> Rare disease (orphan)|Human drugs -> Retsevmo -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients