Rosuvastatin

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Abstract
Rosuvastatin (Crestor®), an HMG-CoA reductase inhibitor (statin), has a favorable pharmacologic profile, including its selective uptake by hepatic cells, hydrophilic nature, and lack of metabolism by cytochrome P450 (CYP) 3A4 isoenzyme. This last property means that the potential for CYP3A4-mediated drug interactions and, as a consequence, adverse events is low in those requiring concomitant therapy with a statin and agents metabolized by CYP3A4. In a broad spectrum of adult patients with dyslipidemias, oral rosuvastatin 5–40mg once daily effectively and rapidly improved lipid profiles in several large, randomized, mainly double-blind, multicenter trials of up to 52 weeks’ duration. After 12 weeks’ treatment, rosuvastatin was significantly (all p < 0.05) more effective at milligram equivalent dosages than atorvastatin, pravastatin, and simvastatin in improving the overall lipid profiles of patients with hypercholesterolemia (intent-to-treat analyses). Moreover, overall a significantly (all p < 0.001) higher proportion of patients achieved National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III low-density lipoprotein-cholesterol (LDL-C) goals with rosuvastatin 10 mg/day than with therapeutic starting dosages of these other statins after 12 weeks’ treatment in pooled analyses. Rosuvastatin treatment for up to 52 weeks was generally well tolerated in patients with dyslipidemias in clinical trials. The most commonly reported treatment-related adverse events were myalgia, constipation, asthenia, abdominal pain, and nausea; these were mostly transient and mild. The incidence of proteinuria or microscopic hematuria with rosuvastatin 10 or 20 mg/day was in vitro and in vivo studies, rosuvastatin typically inhibits HMG-CoA reductase and cholesterol synthesis to a significantly greater extent than other statins. Rosuvastatin is selectively taken up by hepatic cells in vitro and in vivo, with minimal uptake by nonhepatic cells. Rosuvastatin has a high affinity for the predominantly hepatic organic anion transport protein C. Rosuvastatin increases clearance of plasma low-density lipoprotein-cholesterol (LDL-C) by upregulation of hepatic LDL-C receptors and affects LDL production by decreasing hepatic production of very low-density lipoprotein. In healthy volunteers, rosuvastatin 10 mg/day reduced serum LDL-C (44.2%), total cholesterol (31.8%), triglycerides (22.7%), and apolipoprotein (Apo) B (35.3%). Rosuvastatin was equally effective in lowering serum LDL-C following morning or evening administration. Non-lipid-lowering effects, such as improvements in endothelial function, anti-inflammatory effects, vasculo-protective and cardio/cerebro-protective effects, and improvements in neural function have been reported in in vivo and in vitro studies. The Pharmacokinetic properties of rosuvastatin are dose-proportional, with little or no accumulation after repeated administration. Maximum rosuvastatin plasma concentrations of 19–25 μg/L are reached 3–5 hours after administration of a single oral dose of rosuvastatin 40mg in healthy volunteers. The absolute bioavailability of rosuvastatin is approximately 20%. Food decreases the rate of rosuvastatin absorption by 20%, but the extent of absorption remains unchanged. At steady state, the mean volume of distribution of rosuvastatin is approximately 134L. Rosuvastatin is reversibly bound to plasma proteins (88%). Rosuvastatin undergoes very limited metabolism (≈10% of radiolabelled drug recovered as metabolites from urine), with metabolism primarily occurring via cytochrome P450 (CYP) 2C9. N-desmethyl rosuvastatin is the major metabolite. Rosuvastatin undergoes predominantly biliary excretion, with 90% of a single oral dose of radioactive rosuvastatin recovered in the feces (92% as the parent compound). The plasma elimination half-life of rosuvastatin after a single oral dose of rosuvastatin 40mg is 18 24 hours. There were no clinically relevant changes in the pharmacokinetics of rosuvastatin with differences in patient age or gender, time of administration, or mild to moderate renal impairment. However, plasma concentrations of rosuvastatin were increased in patients with severe renal impairment. Rosuvastatin maximum plasma concentration and area under the plasma concentration-time curve values were increased in patients with mild to moderate hepatic impairment. Coadministration of rosuvastatin and ketoconazole, erythromycin, itraconazole (inhibitors of CYP3A4), fenofibrate, fluconazole (metabolized by CYP2C9 and CYP2C19), or digoxin had no clinically relevant effect on the pharmacokinetics of rosuvastatin. Coadministration of rosuvastatin and warfarin increased the International Normalized Ratio. Concomitant rosuvastatin plus cyclosporine or gemfibrozil resulted in a clinically relevant increase in systemic exposure to rosuvastatin. Administration of antacid 2 hours after rosuvastatin avoided clinically relevant decreases in plasma concentrations of rosuvastatin. Administration of contraceptives (ethinyl estradiol and norgestrel) and rosuvastatin increased the plasma concentrations of ethinyl estradiol and norgestrel by 26% and 34%. Treatment with oral rosuvastatin 5–40mg once daily effectively and rapidly improved lipid profiles across a broad spectrum of patients with dyslipidemias in several large, randomized, mainly double-blind, multicenter trials of up to 52 weeks’ duration. In well-designed trials of 6–12 weeks’ duration in patients with hypercholesterolemia, rosuvastatin (5 and 10 mg/day) recipients achieved significantly (all p < 0.05) greater improvements in plasma LDL-C and total cholesterol levels than those receiving atorvastatin 10 mg/day, pravastatin 20 mg/day or simvastatin 20 mg/day, according to primary endpoint intent-to-treat analyses. All other aspects of the lipid profile improved to the same or a greater extent with rosuvastatin treatment than with these other statins, including increases in plasma high-density lipoprotein-cholesterol (HDL-C) levels and reductions in plasma Apo B, triglycerides, and non-HDL-C levels. As assessed in individual trials and pooled analyses, these improvements were in turn reflected in significantly greater improvements in lipid ratios of atherogenic to non-atherogenic lipid components (e. g. LDL-C: HDL-C, non-HDL-C: HDL-C, Apo B: Apo A1 ratios) with rosuvastatin treatment relative to other statins. Notably, rosuvastatin treatment proved effective, irrespective of the patient’s age, gender, postmenopausal status, and/or the presence of type 2 diabetes mellitus with or without metabolic syndrome, hypertension, atherosclerosis, and/or obesity. Pooled analyses indicated that overall a significantly (all p < 0.001) higher proportion of patients achieved National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III LDL-C goals with rosuvastatin 10 mg/day than with therapeutic starting dosages of other statins after 12 weeks’ treatment, with 80% of rosuvastatin 10 mg/day recipients achieving their goals. Rosuvastatin 10 mg/day was significantly (all p < 0.05) more effective than simvastatin 20 mg/day or pravastatin 20 mg/day based on individual NCEP ATP III goals: LDL-C target <100 mg/dL 63%, 22%, and 5% of patients achieved target, respectively; LDL-C target <130 mg/ dL 89%, 74%, and 40%; and LDL-C target <160 mg/dL 99%, 90%, and 88%. Relative to atorvastatin 10 mg/day recipients, significantly more rosuvastatin 10 mg/day recipients achieved their target of <100 mg/dL (60% vs 19% in the atorvastatin group; p < 0.05), although response rates were not statistically different in those with targets of <130 mg/dL (88% vs 80%) or <160 mg/dL (96% vs 91%). Results of the STELLAR (Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin) trial confirmed data from these pooled analyses. In the 16-week MERCURY I (Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY) trial, patients who switched from previous statin treatment to rosuvastatin 10 mg/day achieved significantly (all p < 0.0001) greater reductions in plasma LDL-C than those who continued to receive atorvastatin 10 mg/day (46.2% vs 38.5% reduction), simvastatin 20 mg/day (45.6% vs 37.4%) or pravastatin 40 mg/day (46.6% vs 32.4%). Improvements in lipid parameters that were observed after switching to rosuvastatin were generally reflected in significantly (all p ≤ 0.0001) greater reductions in lipid ratios for LDL-C: HDL-C, non-HDL-C: HDL-C, and Apo B: Apo A1. Furthermore, significantly more patients who switched to rosuvastatin 10 mg/day at 8 weeks achieved NCEP ATP III LDL-C targets than those who remained on existing treatment. In difficult-to-treat patient populations, such as those with type 2 diabetes with mixed dyslipidemia, combining rosuvastatin with fenofibrate enhanced reductions in plasma triglyceride levels versus rosuvastatin monotherapy. However, combining rosuvastatin 40 mg/day with niacin extended-release (ER) 1 g/day had no additional benefit in terms of reduction in atherogenic lipid parameters to those achieved with the equivalent dosage of rosuvastatin monotherapy in patients with Fredrickson type IIb or IV hyperlipidemia, although mean plasma HDL-C levels increased by a significantly greater extent with rosuvastatin 10 mg/day plus niacin ER 2 g/ day than with rosuvastatin 40 mg/day monotherapy (11% vs 24%; p < 0.001). Rosuvastatin was generally well tolerated in clinical trials of up to 1 year’s duration, with tolerability data based on pooled analyses and extension phases of these trials. Overall, in clinical trials the most commonly reported adverse events possibly or probably related to rosuvastatin treatment were myalgia, constipation, asthenia, abdominal pain, and nausea (incidence not reported). Most adverse events were of mild intensity and transient, with 3.7% of 10 275 rosuvastatin recipients discontinuing treatment because of a drug-related adverse event. No rosuvastatin-related deaths occurred during participation in clinical trials. A few rosuvastatin recipients have developed proteinuria (<1% of patients receiving rosuvastatin 10 or 20 mg/day and <1.5% of 40 mg/day recipients) and microscopic hematuria, with these effects generally being mild, mostly transient, possibly tubular in origin, and not associated with acute or progressive deterioration in renal function. There was usually no change or a decrease in mean serum creatinine levels from baseline with rosuvastatin 10–40 mg/day treatment for up to 96 weeks. Notably, in controlled clinical trials with rosuvastatin 5–40 mg/day, 0.2–0.4% of patients experienced elevations in serum creatine phosphokinase (CPK) levels of over 10-fold the upper limit of normal, whereas ≤0.1% of recipients experienced treatment-related myopathy (i. e. muscle aches or weakness plus elevated serum CPK levels of over 10-fold the upper limit of normal); these incidences were similar to those reported with other statins. In clinical trials, rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria occurred with rosuvastatin treatment at the higher-than-recommended 80mg dose. Overall, rosuvastatin 10–40 mg/day had a similar tolerability profile to that of atorvastatin 10–80 mg/day, simvastatin 10–80 mg/day, or pravastatin 10–40 mg/day in controlled clinical trials (nature and incidence of adverse events not reported), with 2.9%, 3.2%, 2.5%, and 2.5% of recipients, respectively, discontinuing treatment because of a treatment-related adverse event. As with rosuvastatin 10 or 20 mg/day, less than 1% of patients experienced a positive dipstick test for proteinuria at the final visit with atorvastatin 10–80 mg/day, simvastatin 10–80 mg/day, and pravastatin 10–40 mg/day, with a numerically higher incidence (<1.5%) in those receiving rosuvastatin 40 mg/day. In addition, rare cases (0.2% of patients) of clinically relevant elevations in serum ALT levels have occurred with rosuvastatin ≤80 mg/day, atorvastatin ≤80 mg/day, simvastatin ≤80 mg/ day, or pravastatin ≤40 mg/day. Rosuvastatin (40 mg/day) was as well tolerated as niacin ER (2 g/day) monotherapy in patients with mixed dyslipidemia, with numerically fewer rosuvastatin (n = 46) than niacin ER recipients (n = 72) experiencing treatment-related adverse events (28.3% vs 59.7%). The most common treatment-related adverse events in the rosuvastatin and niacin ER monotherapy groups were flushing (0% vs 43.1%), pruritus (0% vs 13.9%), rash (0% vs 6.9%), paresthesia (0% vs 2.8%), and myalgia (6.5% vs 1.4%). Limited data also indicate that rosuvastatin (5 or 10 mg/day) plus fenofibrate (201 mg/day) combination therapy was as well tolerated as treatment with the same dosages of the individual agents in a 24-week study. Rosuvastatin is indicated for the treatment of patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson type IIa and IIb) as an adjunct to diet. The recommended dosage is 5–40mg once daily. Rosuvastatin 40 mg/day should only be administered to patients unable to achieve LDL-C goals with 20 mg/day. The drug may be taken without regard to food, with the dosage individualized based on the patient’s response, LDL-C goal, presence of other comorbid conditions, and/or whether the individual is receiving concomitantly administered drugs. Rosuvastatin is also indicated in patients with elevated triglyceride levels (Fredrickson type IV) as an adjunct to diet (recommended dosages not reported in US prescribing information), and in those with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments such as LDL apheresis. Rosuvastatin should be prescribed with caution in patients with predisposing factors for myopathy. Liver function tests should be performed before treatment commences and at key timepoints throughout the treatment. Dosage reduction should be considered for those receiving rosuvastatin 40 mg/day with persistent unexplained proteinuria. Rosuvastatin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases, and in pregnant women and breastfeeding mothers.