Lasofoxifene

413.55

413.55

337G83N988

DTXSID50171037

C80679

G03|G - Genito urinary system and sex hormones

32.7

5.66660

1.150±0.06 g/cm3(Predicted)

110-113°C

572.4±50.0 °C(Predicted)

300ºC

1.613

Refrigerator

1.05E-13mmHg at 25°C

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.

Lasofoxifene is highly bound to plasma proteins (>99%) where it predominantly binds to albumin and α1-acid glycoprotein.

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)|Fablyn is indicated for the treatment of osteoporosis in postmenopausal women at increased risk of fracture. A significant reduction in the incidence of vertebral and non-vertebral fractures but not hip fractures has been demonstrated (see section 5.1).When determining the choice of Fablyn or other therapies, including oestrogens, for a postmenopausal woman, consideration should be given to menopausal symptoms, effects on uterine and breast tissues, and cardiovascular risks and benefits (see section 5.1).|Treatment of osteoporosis in postmenopausal women at increased risk of fracture

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.

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%.|Primarily fecal excretion and secondarily renal elimination as mainly metabolites, with less than 2% excreted in urine as unchanged parent drug.|The apparent volume of distribution in postmenopausal women is 1350L.|The apparent oral clearance (CL/F) of lasofoxifene in postmenopausal women is approximately 6.6 l/hr.

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.|Lasofoxifene has known human metabolites that include (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[[(5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-yl]oxy]oxane-2-carboxylic acid.

Elimination half-life is approximately 6 days.

Lasofoxifene mediates an agonist effect on estrogen receptors expressed on bone to mimic the positive effects of estrogen to reduce the production and lifespan of osteoclasts via altering the NF-kappaB ligand (RANKL)/RANK/osteoprotegerin system, stimulation of osteoblast (the bone forming cells) activity and additional effects on calcium homeostasis. It acts as an antagonist at uterus and mammary glands by suppressing the estrogen signaling in oncogenic pathways and inhibits the downstream gene transcription. A study also suggests that lasofoxifene may also act as an inverse agonist at CB2 cannabinoid receptor which is expressed in bone to inhibit osteoclast formation and resorptive activity.

(-)-cis-5,6,7,8-tetrahydro-6-phenyl-5-(p-(2-(1-pyrrolidinyl)ethoxy)phenyl)-2-naphthol

Human drugs -> Fablyn -> EMA Drug Category|Sex hormones and modulators of the genital system -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans