Raloxifene pharmacokinetics and molecular data

Pharmacokinetics
Mechanism Absorption Distribution Metabolism Elimination Special populations
 * Cirrhosis
 * Pediatric
 * Geriatric
 * Gender
 * Race
 * Renal impairment
 * Hepatic impairment

Mechanism
Raloxifene is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM). The biological actions of Raloxifene are largely mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). The agonistic or antagonistic action of Raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promotors.

Raloxifene appears to act as an estrogen agonist in bone. It decreases bone resorption and bone turnover, increases bone mineral density (BMD) and decreases fracture incidence. Preclinical data demonstrate that Raloxifene is an estrogen antagonist in uterine and breast tissues. These results are consistent with findings in clinical trials, which suggest that Raloxifene lacks estrogen-like effects on the uterus and breast tissue. Return to top

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%. 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. Return to top

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 α1-acid glycoprotein, but not to sex-steroid binding globulin.Return to top

Metabolism
Biotransformation and disposition of Raloxifene in humans have been determined following oral administration of 14C-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. Unconjugated Raloxifene comprises less than 1% of the total radiolabeled material in plasma. The terminal log-linear portions of the plasma concentration curves for raloxifene and the glucuronides are generally parallel. This is consistent with interconversion of raloxifene and the glucuronide metabolites.

Following intravenous administration, Raloxifene is cleared at a rate approximating hepatic blood flow. Apparent oral clearance is 44.1 L/kg•hr. Raloxifene and its glucuronide conjugates are interconverted by reversible systemic metabolism and enterohepatic cycling, thereby prolonging its plasma elimination half-life to 27.7 hours after oral dosing.

Results from single oral doses of Raloxifene predict multiple-dose pharmacokinetics. Following chronic dosing, clearance ranges from 40 to 60 L/kg•hr. Increasing doses of Raloxifene HCl (ranging from 30 to 150 mg) result in slightly less than a proportional increase in the area under the plasma time concentration curve (AUC). Return to top

Elimination
Primarily excreted in feces. Less than 0.2% is excreted unchanged in urine. Cl (oral) is 44.1 L/kg/h and t ½ is 27.7 to 32.5 h. Chronic dosing Cl is 40 to 60 L/kg/h. Less than 6% of the Raloxifene dose is eliminated in urine as glucuronide conjugates. Return to top

Cirrhosis
Plasma concentrations increase 2.5 times. Safety and efficacy have not been evaluated any further. Return to top

Pediatric
The pharmacokinetics of Raloxifene has not been evaluated in a pediatric population. Return to top

Geriatric
No differences in Raloxifene pharmacokinetics were detected with regard to age (range 42 to 84 years). Return to top

Gender
Total extent of exposure and oral clearance, normalized for lean body weight, are not significantly different between age-matched female and male volunteers. Return to top

Race
Pharmacokinetic differences due to race have been studied in 1712 women, including 97.5% White, 1.0% Asian, 0.7% Hispanic, and 0.5% Black in the osteoporosis treatment trial and in 1053 women, including 93.5% White, 4.3% Hispanic, 1.2% Asian, and 0.5% Black in the osteoporosis prevention trials. There were no discernible differences in Raloxifene plasma concentrations among these groups; however, the influence of race cannot be conclusively determined. Return to top

Renal impairment
In the osteoporosis treatment and prevention trials, Raloxifene concentrations in women with mild renal impairment are similar to women with normal creatinine clearance. When a single dose of 120 mg Raloxifene HCl was administered to 10 renally impaired males [7 moderate impairment (CrCl = 31 – 50 mL/min); 3 severe impairment (CrCl ≤30 mL/min)] and to 10 healthy males (CrCl >80 mL/min), plasma Raloxifene concentrations were 122% (AUC0-∞) higher in renally impaired patients than those of healthy volunteers. Raloxifene should be used with caution in patients with moderate or severe renal impairment. Return to top

Hepatic impairment
The disposition of Raloxifene was compared in 9 patients with mild (Child-Pugh Class A) hepatic impairment (total bilirubin ranging from 0.6 to 2 mg/dL) to 8 subjects with normal hepatic function following a single dose of 60 mg Raloxifene HCl. Apparent clearance of Raloxifene was reduced 56% and the half-life of Raloxifene was not altered in patients with mild hepatic impairment. Plasma Raloxifene concentrations were approximately 150% higher than those in healthy volunteers and correlated with total bilirubin concentrations. The pharmacokinetics of Raloxifene has not been studied in patients with moderate or severe hepatic impairment. Raloxifene should be used with caution in patients with hepatic impairment. Return to top