LOXO-292

Absorption

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 Cmax of 2,980 (CV 53%) and AUC0-24h of 51,600 (CV 58%). The absolute bioavailability is between 60 and 82% (mean 73%), and the median tmax is two hours. Food has no apparent effect on the AUC or Cmax of selpercatinib. Patients with hepatic impairment display a concomitant increase in AUC0-INF for mild (7%), moderate (32%), and severe (77%) impairment.

Toxicity

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.

The Uses of LOXO-292

Selpercatinib is a small molecule protein kinase inhibitor which may be used in the treatment of cancer.

Indications

Selpercatinib is approved to treat:
Selpercatinib is currently approved for these indications under an accelerated approval scheme and continued approval may be contingent on future confirmatory trials.

Background

Selpercatinib is a kinase inhibitor with enhanced specificity for RET tyrosine kinase receptors (RTKs) over other RTK classes. Enhanced RET (Rearranged during transfection) oncogene expression is a hallmark of many cancers. Although multikinase inhibitors, including cabozantinib, ponatinib, sorafenib, sunitinib, and vandetanib, have shown efficacy in RET-driven cancers, their lack of specificity is generally associated with substantial toxicity. Selpercatinib (LOXO-292) and pralsetinib (BLU-667) represent the first generation of specific RET RTK inhibitors for the treatment of RET-driven cancers.
Although selpercatinib is currently still under investigation in clinical trial NCT04211337, it was granted accelerated FDA approval on May 8, 2020, for specific RET-driven cancer indications. It is currently marketed under the brand name RETEVMO? by Loxo Oncology Inc. Selpercatinib is also approved by the European Commission.

brand name

Retevmo

General Description

Class: receptor tyrosine kinase; Treatment: RET-altered lung/thyroid cancers; Other name: ARRY-192, LOXO-292; Oral bioavailability = 73%; Elimination half-life = 32 h; Protein binding = 97%

Pharmacokinetics

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.

Side Effects

Selpercatinib can cause serious side effects including liver toxicity, high blood pressure, heart rhythm changes due to prolongation of heart electrical activity (QT prolongation), bleeding, allergic reactions, impaired wound healing and harm to an unborn baby.

Selpercatinib may cause harm to a developing fetus or a newborn baby.

Metabolism

Selpercatinib is predominantly metabolized in the liver by CYP3A4.

storage

Store at -20°C

Dosage

The recommended selpercatinib dose based on body weight is: (1) Less than 50 kg: 120 mg orally twice daily (2) 50 kg or greater: 160 mg orally twice daily