Lasofoxifene

Absorption

Peak plasma concentrations (Cmax) were reached in about 6.0 to 7.3 hours . Displays higher oral bioavailability compared to other SERMs with increased resistance to intestinal glucuronidation due to nonpolar tetrahydronaphthalene structure . In a comparative study in the rat, lasofoxifene showed bioavailability of 62% .

Toxicity

Lasofoxifene increases the risk of venous thromboembolism driven by increased risk of deep vein thrombosis. Other adverse effects include hot flushes, muscle spasms and vaginal bleeding.

Chemical properties

Off-White Solid

The Uses of Lasofoxifene

A next-generation selective estrogen receptor modulator for treating disorders associated with increased bone turnover and osteopenia.

Background

Lasofoxifene is a non-steroidal 3rd generation selective estrogen receptor modulator (SERM) that selectively binds to both ERα and ERβ with high affinity. It is a naphthalene derivative marketed for prevention and treatment of osteoporosis and for the treatment of vaginal atrophy. It was initially developed as Oporia by Pfizer as a treatment for postmenopausal osteoporosis and vaginal atrophy, in which were both rejected for approval by FDA. Later Fablyn was developed as a result of a research collaboration between Pfizer and Ligand Pharmaceuticals with a newly submitted New Drug Application in 2008. It gained approval by European Commission in March 2009. Ligand Pharmaceuticals signed a license agreement with Sermonix Pharmaceuticals for the development and commercialization of oral lasofoxifene in the USA.

Indications

Investigated for use/treatment in postmenopausal osteoporosis to reduce the risk of both vertebral and novertebral fractures, as well as address other postmenopausal conditions, including reduction in risk of breast cancer and treatment of vulvar and vaginal atrophy (VVA)

What are the applications of Application

Lasofoxifene is a non-steroidal selective estrogen receptor modulator

Definition

ChEBI: Lasofoxifene is a member of the class of tetralins that is 5,6,7,8-tetrahydronaphthalen-2-ol in which the hydrogens at positions 5 and 6 are replaced by 4-[2-(pyrrolidin-1-yl)ethoxy]phenyl and phenyl groups, respectively (the 5R,6S-stereoisomer). It is a selective estrogen receptor modulator indicated for the prevention and treatment of osteoporosis in post-menopausal women. It has a role as an antineoplastic agent, a cardioprotective agent, an estrogen receptor agonist, an estrogen receptor antagonist and a bone density conservation agent. It is a member of tetralins, an aromatic ether, a member of naphthols and a N-alkylpyrrolidine.

Pharmacokinetics

Lasofoxifene exhibits both significant estrogenic and antiestrogenic activity both in vitro and in vivo, targeting any tissues that possess ERs, such as bone, uterus, breast, blood vessels, and liver. Binding assays demonstrated high affinity of the compound for both ERα and ERβ in a tissue-dependent manner. It mimics the effects of estradiol with varying agonist and antagonist effects.

Clinical Use

Lasofoxifene is a very potent second-generation SERM currently in phase III clinical trials for the treatment and prevention of osteoporosis in postmenopausal women.

Metabolism

Phase I oxidation via hepatic CYP3A4/CYP3A5 and CYP2D6 accounts for nearly half of total metabolism of lasofoxifene. Phase II conjugation reactions include glucuronidation and sulfation. Its glucuronidation is catalyzed by UGTs that are expressed in both the liver (UGT1A1, UGT1A3, UGT1A6, and UGT1A9) and the intestine (UGT1A8 and UGT1A10). Further metabolites of lasofoxifene detected in plasma are the glucuronide of a hydroxylated metabolite, and the methylated catechols .