Crestor (Rosuvastatin Calcium) - Description and Clinical Pharmacology

Recent Major Changes

DESCRIPTION

CRESTOR (rosuvastatin calcium) is a synthetic lipid-lowering agent for oral administration.

The chemical name for rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt with the following structural formula:

The empirical formula for rosuvastatin calcium is (C₂₂H₂₇FN₃O₆S)₂Ca and the molecular weight is 1001.14. Rosuvastatin calcium is a white amorphous powder that is sparingly soluble in water and methanol, and slightly soluble in ethanol. Rosuvastatin calcium is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7.0.

Inactive Ingredients: Each tablet contains: microcrystalline cellulose NF, lactose monohydrate NF, tribasic calcium phosphate NF, crospovidone NF, magnesium stearate NF, hypromellose NF, triacetin NF, titanium dioxide USP, yellow ferric oxide, and red ferric oxide NF.

CLINICAL PHARMACOLOGY

Mechanism of Action

CRESTOR is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3- methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. In vivo studies in animals, and in vitro studies in cultured animal and human cells have shown rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the target organ for cholesterol lowering. In in vivo and in vitro studies, rosuvastatin produces its lipid-modifying effects in two ways. First, it increases the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.

Pharmacokinetics

• Absorption: In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both C_max and AUC increased in approximate proportion to CRESTOR dose. The absolute bioavailability of rosuvastatin is approximately 20%.

  Administration of CRESTOR with food did not affect the AUC of rosuvastatin.

  The AUC of rosuvastatin does not differ following evening or morning drug administration.

• Distribution: Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

• Metabolism: Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound.

• Excretion: Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). The elimination half-life (t_1/2) of rosuvastatin is approximately 19 hours.

  After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.

• Race: A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic, and Black or Afro-Caribbean groups. However, pharmacokinetic studies, including one conducted in the US, have demonstrated an approximate 2-fold elevation in median exposure (AUC and C_max) in Asian subjects when compared with a Caucasian control group.

• Gender: There were no differences in plasma concentrations of rosuvastatin between men and women.

• Geriatric: There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years).

• Renal Impairment: Mild to moderate renal impairment (CL_cr ≥ 30 mL/min/1.73 m²) had no influence on plasma concentrations of rosuvastatin. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3-fold) in patients with severe renal impairment (CL_cr < 30 mL/min/1.73 m²) not receiving hemodialyis compared with healthy subjects (CL_cr > 80 mL/min/1.73 m²).

• Hemodialysis: Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function.

• Hepatic Impairment: In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased.

  In patients with Child-Pugh A disease, C_max and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, C_max and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function.

Drug-Drug Interactions:

Cytochrome P450 3A4

Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent.

Table 3. Effect of Co-administered Drugs on Rosuvastatin Systemic Exposure

Co-administered drug and dosing regimen	Rosuvastatin
	Dose (mg) 1	Change in AUC	Change in Cmax
Cyclosporine – stable dose required (75 mg – 200 mg BID)	10 mg QD for 10 days	↑ 7-fold 2	↑ 11-fold
Gemfibrozil 600 mg BID for 7 days	80 mg	↑ 1.9-fold	↑ 2.2-fold
Lopinavir/ritonavir combination 400 mg/100 mg BID for 10 days	20 mg QD for 7 days	↑ 2-fold	↑ 5-fold
Fenofibrate 67 mg TID for 7 days	10 mg	↑ 7%	↑ 21%
Aluminum & magnesium hydroxide combination antacid Administered simultaneously Administered 2 hours apart	40 mg 40 mg	↓ 54% ↓ 22%	↓ 50% ↓ 16%
Erythromycin 500 mg QID for 7 days	80 mg	↓ 20%	↓ 31%
Ketoconazole 200 mg BID for 7 days	80 mg	↑ 2%	↓ 5%
Itraconazole 200 mg QD for 5 days	10 mg 80 mg	↑ 39% ↑ 28%	↑ 36% ↑ 15%
Fluconazole 200 mg QD for 11 days	80 mg	↑ 14%	↑ 9%

Table 4. Effect of Rosuvastatin Co-Administration on Systemic Exposure To Other Drugs

Rosuvastatin Dosage Regimen	Co-administered Drug
	Name and Dose	Change in AUC	Change in Cmax
40 mg QD for 10 days	Warfarin 1 25 mg single dose	R- Warfarin ↑ 4% S-Warfarin ↑6%	R-Warfarin ↓ 1% S-Warfarin 0%
40 mg QD for 12 days	Digoxin 0.5 mg single dose	↑ 4%	↑ 4%
40 mg QD for 28 days	Oral Contraceptive (ethinyl estradiol 0.035 mg & norgestrel 0.180, 0.215 and 0.250 mg) QD for 21 Days	EE ↑ 26% NG ↑ 34%	EE ↑ 25% NG ↑ 23%
EE = ethinyl estradiol, NG = norgestrel

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of uterine stromal polyps was significantly increased in females at 80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC. Increased incidence of polyps was not seen at lower doses.

In a 107-week carcinogenicity study in mice given 10, 60, 200 mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures 20 times the human exposure at 40 mg/day based on AUC. An increased incidence of hepatocellular tumors was not seen at lower doses.

Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli, the mouse lymphoma assay, and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test.

In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month, spermatidic giant cells were seen. Spermatidic giant cells were observed in monkeys after 6-month treatment at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area. Similar findings have been seen with other drugs in this class.

Animal Toxicology and/or Pharmacology

Embryo-fetal Development

Rosuvastatin crosses the placenta and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. A higher fetal tissue distribution (25% maternal plasma concentration) was observed in rabbits after a single oral gavage dose of 1 mg/kg on gestation day 18.

In female rats given oral gavage doses of 5, 15, 50 mg/kg/day rosuvastatin before mating and continuing through day 7 postcoitus results in decreased fetal body weight (female pups) and delayed ossification at the high dose (systemic exposures 10 times the human exposure at 40 mg/day based on AUC).

In pregnant rats given oral gavage doses of 2, 10, 50 mg/kg/day from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred in groups given 50 mg/kg/day, systemic exposures ≥ 12 times the human exposure at 40 mg/day based on body surface area.

In pregnant rabbits given oral gavage doses of 0.3, 1, 3 mg/kg/day from gestation day 6 to lactation day 18 (weaning), exposures equivalent to the human exposure at 40 mg/day based on body surface area, decreased fetal viability and maternal mortality was observed.

Rosuvastatin was not teratogenic in rats at ≤ 25 mg/kg/day or in rabbits ≤ 3 mg/kg/day (systemic exposures equivalent to the human exposure at 40 mg/day based on AUC or body surface area, respectively).

Central Nervous System Toxicity

CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Edema, hemorrhage, and partial necrosis in the interstitium of the choroid plexus was observed in a female dog sacrificed moribund at day 24 at 90 mg/kg/day by oral gavage (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Corneal opacity was seen in dogs treated for 52 weeks at 6 mg/kg/day by oral gavage (systemic exposures 20 times the human exposure at 40 mg/day based on AUC). Cataracts were seen in dogs treated for 12 weeks by oral gavage at 30 mg/kg/day (systemic exposures 60 times the human exposure at 40 mg/day based on AUC). Retinal dysplasia and retinal loss were seen in dogs treated for 4 weeks by oral gavage at 90 mg/kg/day (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Doses ≤30 mg/kg/day (systemic exposures ≤60 times the human exposure at 40 mg/day based on AUC) did not reveal retinal findings during treatment for up to one year.

CLINICAL STUDIES

Hyperlipidemia and Mixed Dyslipidemia

CRESTOR reduces total-C, LDL-C, ApoB, nonHDL-C, and TG, and increases HDL-C, in adult patients with hyperlipidemia and mixed dyslipidemia.

Dose-Ranging Study: In a multicenter, double-blind, placebo-controlled, dose-ranging study in patients with hyperlipidemia CRESTOR given as a single daily dose for 6 weeks significantly reduced total-C, LDL-C, nonHDL-C, and ApoB, across the dose range (Table 5).

Table 5. Dose-Response in Patients With Hyperlipidemia (Adjusted Mean % Change From Baseline at Week 6)

Dose	N	Total-C	LDL-C	Non-HDL-C	ApoB	TG	HDL-C
Placebo	13	-5	-7	-7	-3	-3	3
CRESTOR 5 mg	17	-33	-45	-44	-38	-35	13
CRESTOR 10 mg	17	-36	-52	-48	-42	-10	14
CRESTOR 20 mg	17	-40	-55	-51	-46	-23	8
CRESTOR 40 mg	18	-46	-63	-60	-54	-28	10

Active-Controlled Study: CRESTOR was compared with the HMG-CoA reductase inhibitors atorvastatin, simvastatin, and pravastatin in a multicenter, open-label, dose-ranging study of 2,240 patients with hyperlipidemia or mixed dyslipidemia. After randomization, patients were treated for 6 weeks with a single daily dose of either CRESTOR, atorvastatin, simvastatin, or pravastatin (Figure 1 and Table 6).

Figure 1. Percent LDL-C Change by Dose of CRESTOR,

Atorvastatin, Simvastatin, and Pravastatin

at Week 6 in Patients with Hyperlipidemia or Mixed Dyslipidemia