Evista

[Raloxifene]

Clinical Pharmacology
CLINICAL PHARMACOLOGY

Mechanism of Action

Decreases in estrogen levels after oophorectomy or menopause lead to increases in bone resorption and accelerated bone loss. Bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses. In addition to loss of estrogen, this imbalance between resorption and formation may be due to age-related impairment of osteoblasts or their precursors.

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In some women, these changes will eventually lead to decreased bone mass, osteoporosis, and increased risk for fractures, particularly of the spine, hip, and wrist. Vertebral fractures are the most common type of osteoporotic fracture in postmenopausal women. The biological actions of raloxifene are largely mediated through binding to estrogen receptors.

This binding results in activation of certain estrogenic pathways and blockade of others. Thus, raloxifene is a SERM. Raloxifene decreases resorption of bone and reduces biochemical markers of bone turnover to the premenopausal range. These effects on bone are manifested as reductions in the serum and urine levels of bone turnover markers, decreases in bone resorption based on radiocalcium kinetics studies, increases in bone mineral density (BMD), and decreases in incidence of fractures.

Raloxifene also has effects on lipid metabolism. Raloxifene decreases total and LDL cholesterol levels but does not increase triglyceride levels (see PRECAUTIONS). It does not change total HDL cholesterol levels. Preclinical data demonstrate that raloxifene is an estrogen antagonist in uterine and breast tissues. Clinical trial data (through a median of 42 months) suggest that EVISTA lacks estrogen-like effects on the uterus and breast tissue.

Pharmacokinetics

The disposition of raloxifene has been evaluated in more than 3000 postmenopausal women in selected raloxifene osteoporosis treatment and prevention clinical trials using a population approach. Pharmacokinetic data were also obtained in conventional pharmacology studies in 292 postmenopausal women. Raloxifene exhibits high within-subject variability (approximately 30% coefficient of variation) of most pharmacokinetic parameters.

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