Lasofoxifene Advanced Drug Monograph

Lasofoxifene Report

Name: Lasofoxifene Name (English): Lasofoxifene DrugBank ID: DB06202 Type: Small Molecule CAS Number: 180916-16-9

Lasofoxifene is a non-steroidal, third-generation selective estrogen receptor modulator (SERM). It selectively binds to both estrogen receptor alpha (ER$\alpha$) and beta (ER$\beta$) with high affinity, exhibiting both estrogenic and antiestrogenic activity depending on the tissue.

Pharmacology: Lasofoxifene acts as an estrogen agonist in bone, mimicking the effects of estrogen to reduce bone resorption and increase bone mineral density. It acts as an antagonist in the uterus and mammary glands by suppressing estrogen signaling.

Indications: It is marketed in some countries for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy in postmenopausal women. Lasofoxifene is also being investigated for the treatment of estrogen receptor-positive metastatic breast cancer, particularly in patients with ESR1 mutations, and for dyspareunia associated with vaginal atrophy.

Pharmacokinetics: Lasofoxifene demonstrates higher oral bioavailability compared to other SERMs. Peak plasma concentrations are reached in approximately 6-7 hours. It is primarily metabolized by hepatic CYP3A4/CYP3A5 and CYP2D6 enzymes, followed by glucuronidation and sulfation. The elimination half-life is approximately 6 days, with primarily fecal excretion of metabolites.

Clinical Trials: Lasofoxifene has been evaluated in phase II and phase III clinical trials for osteoporosis and breast cancer. Studies like ELAINE 1 and ELAINE 2 investigated its efficacy in advanced or metastatic ER+/HER2- breast cancer with ESR1 mutations. The phase III ELAINE 3 trial is ongoing, comparing lasofoxifene plus abemaciclib to fulvestrant plus abemaciclib in patients with ER+/HER2- metastatic breast cancer harboring an ESR1 mutation.

Adverse Effects: Common adverse effects include hot flushes and muscle spasms. Lasofoxifene has been associated with an increased risk of venous thromboembolic events, including deep vein thrombosis.

Chemical and Physical Properties:

• Molecular Formula: $\mathrm{C_{28}H_{31}NO_2}$
• Molecular Weight: 413.55 g/mol
• Appearance: Off-white solid