Evista Clinical Pharmacology

Drug Library
Evista - Clinical Pharmacology [Raloxifene]

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.

Table 1 summarizes the pharmacokinetic parameters of raloxifene. Absorption Raloxifene is absorbed rapidly after oral administration. Approximately 60% of an oral dose is absorbed, but presystemic glucuronide conjugation is extensive. Absolute bioavailability of raloxifene is 2.0%. The time to reach average maximum plasma concentration and bioavailability are functions of systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites.

Administration of raloxifene HCl with a standardized, high-fat meal increases the absorption of raloxifene (Cmax 28% and AUC 16%), but does not lead to clinically meaningful changes in systemic exposure. EVISTA can be administered without regard to meals. Distribution Following oral administration of single doses ranging from 30 to 150 mg of raloxifene HCl, the apparent volume of distribution is 2348 L/ kg and is not dose dependent. Raloxifene and the monoglucuronide conjugates are highly (95%) bound to plasma proteins.

Raloxifene binds to both albumin and 1-acid glycoprotein, but not to sex-steroid binding globulin.

Metabolism Biotransformation and disposition of raloxifene in humans have been determined following oral administration of 14 C-labeled raloxifene. Raloxifene undergoes extensive first-pass metabolism to the glucuronide conjugates: raloxifene-4 -glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4 -diglucuronide. No other metabolites have been detected, providing strong evidence that raloxifene is not metabolized by cytochrome P450 pathways.