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Pharmacology: Pharmacodynamics: Mechanism of action: Rosuvastatin is a selective, potent 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. Triglycerides (TG) and cholesterol in the liver are incorporated, with apolipoprotein B (ApoB), into very low density lipoprotein (VLDL) and released into the plasma for delivery to peripheral tissues. VLDL particles are TG-rich. Cholesterol-rich low density lipoprotein (LDL) is formed from VLDL and is cleared primarily through the high affinity LDL receptor in the liver.
Rosuvastatin produces its lipid-modifying effects in two ways; it increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.
High density lipoprotein (HDL), which contains ApoA-I is involved, amongst other things, in transport of cholesterol from tissues back to the liver (reverse cholesterol transport).
The involvement of LDL-C in atherogenesis has been well documented. Epidemiological studies have established that high LDL-C, TG, low HDL-C and ApoA-I have been linked to a higher risk of cardiovascular disease. Intervention studies have shown the benefits on mortality and CV event rates of lowering LDL-C and TG or raising HDL-C. More recent data has linked the beneficial effects of HMG-CoA reductase inhibitors to lowering of non-HDL (i.e. all circulating cholesterol not in HDL) and ApoB or reducing the ApoB/ApoA-I ratio.
Clinical efficacy: Rosuvastatin (ROSUKON-20) reduces elevated LDL-cholesterol, total cholesterol and triglycerides and increases HDL-cholesterol. It also lowers ApoB, nonHDL-C, VLDL-C, VLDL-TG and increases ApoA-I (see Tables 1 and 2).
Rosuvastatin (ROSUKON-20) also lowers the LDL-C/HDL-C, total C/HDL-C, nonHDL-C/HDL-C and ApoB/ApoA-I ratios.
A therapeutic response to Rosuvastatin (ROSUKON-20) is evident within 1 week of commencing therapy and 90% of maximum response is usually achieved in 2 weeks. The maximum response is usually achieved by 4 weeks and is maintained after that. (See Tables 1 and 2.)
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Click on icon to see table/diagram/imageThe data in Tables 1 and 2 are confirmed by the broader clinical programme of over 5,300 patients given Rosuvastatin (ROSUKON-20).
In a study of patients with heterozygous familial hypercholesterolaemia, 435 subjects were given Rosuvastatin (ROSUKON-20) from 20 mg to 80 mg in a force-titration design. All doses of Rosuvastatin (ROSUKON-20) showed a beneficial effect on lipid parameters and treatment to target goals. Following titration to 40 mg (12 weeks of treatment) LDL-C was reduced by 53%.
In a force-titration open label study, 42 patients with homozygous familial hypercholesterolaemia were evaluated for their response to Rosuvastatin (ROSUKON-20) 20 - 40 mg titrated at a 6 week interval. In the overall population, the mean LDL-C reduction was 22%. In the 27 patients with at least a 15% reduction by week 12 (considered to be the responder population), the mean LDL-C reduction was 26% at the 20 mg dose and 30% at the 40 mg dose. Of the 13 patients with an LDL-C of less than 15%, 3 had no response or an increase in LDL-C.
In the METEOR study, the effect of rosuvastatin 40 mg on the progression of atherosclerosis was assessed by B-mode ultrasound of the carotid arteries. In this multi-center, double blind, placebo-controlled clinical trial, 984 subjects at low risk for coronary heart disease (defined as Framingham risk <10% over ten years) and with a mean LDL-C of 154.5 mg/dL but with subclinical atherosclerosis as detected by CIMT (Carotid Intima Media Thickness) were randomized in a 5:2 ratio to treatment with either rosuvastatin 40 mg or placebo for 2 years. Rosuvastatin significantly slowed the progression of carotid atherosclerosis compared to placebo. The difference in the rate of change in the maximum CIMT of all 12 carotid artery sites between rosuvastatin-treated patients and placebo-treated patients was -0.0145 mm/year (95% CI -0.0196, -0.0093; p<0.0001). The change from baseline for the rosuvastatin group was -0.0014 mm/year (95% CI -0.0041, 0.0014), but was not significantly different from zero (p=0.3224). The beneficial effects of rosuvastatin were consistent across all 4 secondary CIMT endpoints. There was significant progression in the placebo group (+0.0131 mm/year; 95% CI 0.0087, 0.0174; p<0.0001). In the rosuvastatin group, 52.1% of patients demonstrated an absence of disease progression (i.e. regressed) compared to 37.7% of patients in the placebo group (p=0.0002). Rosuvastatin 40 mg was well-tolerated and the data were consistent to the established safety profile for rosuvastatin.
In a randomized, multicenter, double-blind crossover study, 32 patients (27 with ε2/ε2 genotype and 4 with apo E mutation [Arg145Cys]) with dysbetalipoproteinaemia (Fredrickson type III) received rosuvastatin 10 or 20 mg daily for 6 weeks. Rosuvastatin reduced non-HDL-C (primary end point) and circulating remnant lipoprotein levels. Results are shown in the table as follows. (See Table 3.)
Click on icon to see table/diagram/imageIn the ASTEROID Trial, the effect of very intensive statin therapy using rosuvastatin 40 mg on regression of coronary atherosclerosis was determined by IVUS imaging. In this prospective, open-label, blinded endpoint, multi-centre trial, 507 patients who underwent coronary angiography and with evidence of coronary artery disease (at least 1 obstruction with >20% angiographic luminal diameter narrowing in any coronary vessel) were given rosuvastatin 40 mg. Atheroma burden at baseline and after 24 months of treatment was assessed using IVUS ultrasound. Each pair of baseline and follow-up IVUS assessments was analyzed in a blinded fashion.
Analysis of the 349 patients with evaluable IVUS showed that rosuvastatin significantly reduced percent atheroma volume in the entire target vessel by 0.98%, with a median of 0.79% (p<0.001) and 63.6% of patients showed regression while 36.4% showed progression. The mean change in atheroma volume in the most diseased 10-mm subsegment was -6.1 mm3, median change of -5.6 mm3 (p<0.001). This change represents a median reduction of 9.1% in atheroma volume, with 78.1% of patients demonstrated progression and 29.1% showed progression. Change in total atheroma volume showed 6.8% median reduction; with a mean reduction of -14.7 mm3, with a median of 12.5 mm3 (p<0.001). Adverse events were infrequent and similar to other statin trials.
The ASTEROID trial demonstrated that patients given very high intensity statin therapy using rosuvastatin 40 mg had significant regression of atherosclerosis for all three prespecified IVUS measures of disease burden. Patients treated with rosuvastatin 40 mg achieved a 53.2% LDL-C reduction, the lowest ever observed in a statin atherosclerosis progression trial and a 14.7% HDL-C increase, which also exceeded effects reported in previous statin trials. Nonetheless, further studies are needed to determine the effect of the observed changes on clinical outcome.
The Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA) was a randomized, double-blind, placebo controlled study in 5011 subjects with chronic symptomatic systolic heart failure treated with rosuvastatin 10 mg (n=2514) or placebo (n=2497) for a mean treatment duration of 2.5 years. When rosuvastatin 10 mg was added to extensive pharmacologic background therapy in these subjects, a non-significant 8% decrease versus placebo in the primary endpoint of cardiovascular death, non-fatal MI or non-fatal stroke was observed (HR 0.92, 95% CI 0.83 to 1.02; p=0.12).
The safety profile of the subjects taking rosuvastatin 10 mg was comparable to that of the subjects taking placebo. From the trial, 1.8% of rosuvastatin-treated subjects versus 1.7% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, pruritus, rash, and dizziness. Adverse reactions reported in ≥2% of patients and at a rate greater than or equal to placebo may be found in Table 4. (See Table 4.)
Click on icon to see table/diagram/imageRosuvastatin (ROSUKON-20) is effective in a wide variety of patient populations with hypercholesterolaemia, with and without hypertriglyceridaemia, regardless of race, sex or age and in special populations such as diabetics or patients with familial hypercholesterolaemia.
In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, the effect of Rosuvastatin (ROSUKON-20) (rosuvastatin calcium) on the occurrence of major atherosclerotic cardiovascular (CV) disease events was assessed in 17,802 men (≥50 years) and women (≥60 years) who had no established cardiovascular disease, LDL-C levels <130 mg/dL (3.3 mmol/l) and hs-CRP levels ≥2 mg/L. The study population had an estimated baseline coronary heart disease risk of 11.3% over 10 years based on the Framingham risk criteria and included a high percentage of patients with additional risk factors such as hypertension (58%), low HDL-C levels (23%), cigarette smoking (16%) or a family history of premature CHD (12%). Study participants were randomly assigned to placebo (n=8901) or rosuvastatin 20 mg once daily (n=8901) and were followed for a mean duration of 2 years.
The primary endpoint was a composite endpoint consisting of the time-to-first occurrence of any of the following CV events: CV death, non-fatal myocardial infarction, non-fatal stroke, unstable angina or an arterial revascularization procedure.
Rosuvastatin significantly reduced the risk of CV events (252 events in the placebo group vs. 142 events in the rosuvastatin group) with a statistically significant (p<0.001) relative risk reduction of 44% (see figure). The benefit was apparent within the first 6 months of treatment. The risk reduction was consistent across multiple predefined population subsets based on assessments of age, sex, race, smoking status, family history of premature CHD, body mass index, LDL-C, HDL-C or hsCRP levels at the time of entry into the study. There was a statistically significant 48% reduction in the combined endpoint of CV death, stroke and myocardial infarction (HR: 0.52, 95% CI: 0.40-0.68, p<0.001), a 54% reduction in fatal or nonfatal myocardial infarction (HR: 0.46, 95% CI: 0.30-0.70) and a 48% reduction in fatal or nonfatal stroke. Total mortality was reduced 20% in the rosuvastatin group (HR: 0.80, 95% CI: 0.67-0.97, p=0.02). (See figure.)
Click on icon to see table/diagram/imageThe safety profile for subjects taking rosuvastatin 20 mg was generally similar to that of subjects taking placebo. There were 1.6% of rosuvastatin and 1.8% of placebo subjects who withdrew from the trial due to an adverse event, irrespective of treatment causality. The most common adverse reactions that led to treatment discontinuation were: myalgia (0.3% rosuvastatin, 0.2% placebo), abdominal pain (0.03% rosuvastatin, 0.02% placebo) and rash (0.03% rosuvastatin, 0.03% placebo). Adverse reactions reported in ≥ 2% of patients and at a rate greater than or equal to placebo were myalgia (7.6% rosuvastatin, 6.6% placebo), constipation (3.3% rosuvastatin, 3.0% placebo) and nausea (2.4% rosuvastatin, placebo 2.3%).
In JUPITER, there was a statistically significant increase in the frequency of diabetes mellitus reported by investigators; 2.8% of patients in the rosuvastatin group and 2.3% of patients in the placebo group (HR: 1.27, 95% CI: 1.05-1.53, p=0.015). The difference between treatment groups (rosuvastatin versus placebo) in mean HbA1c change from baseline was approximately 0.1%. A post hoc analysis of this study suggests that the risk of development of diabetes on rosuvastatin therapy is limited to patients already at high risk of developing diabetes. The cardiovascular and mortality benefits of rosuvastatin therapy exceeded the diabetes hazard in the trial population as a whole as well as in participants at increased risk of developing diabetes (see Precautions and Adverse Reactions).
Children and Adolescents with Hypercholesterolaemia: In a double blind, randomized, multi-centre, placebo-controlled, 12-week study (n=176, 97 male and 79 female) followed by a 40-week (n=173, 96 male and 77 female), open label, rosuvastatin dose titration phase, 10-17 years of age (Tanner stage II-V, females at least 1 year post-menarche) with heterozygous familial hypercholesterolaemia received rosuvastatin 5, 10 or 20 mg or placebo daily for 12 weeks and then all received rosuvastatin daily for 40 weeks. At study entry, approximately 30% of the patients were 10-13 years and approximately 17%, 18%, 40%, and 25% were Tanner stage II, III, IV, and V respectively.
Rosuvastatin reduced LDL-C (primary end point), total cholesterol and ApoB levels. Results are shown in Table 5 as follows. (See Table 5.)
Click on icon to see table/diagram/imageAt the end of the 40 week, open label, titration to goal, dosing up to a maximum of 20 mg once daily, 70 of 173 patients (40.5%) had achieved the LDL-C goal of less than 110 mg/dL (2.8 mmol/L).
After 52 weeks of study treatment, no effect on growth or sexual maturation was detected (see Precautions).
Rosuvastatin was also studied in a 2-year open-label, titration-to-goal study in 198 children with heterozygous familial hypercholesterolaemia aged 6 to 17 years (88 male and 110 female, Tanner stage <II-V). The starting dose for all patients was 5 mg rosuvastatin once daily. Patients aged 6 to 9 years (n=64) could titrate to a maximum dose of 10 mg once daily and patients aged 10 to 17 years (n=134) to a maximum dose of 20 mg once daily.
After treatment, 74 of 197 patients (37.6%) in this study achieved the LDL-C goal of less than 110 mg/dL (2.8 mmol/L). All age groups showed statistically significant reductions in LDL-C from baseline values.
Rosuvastatin 5 mg, 10 mg, and 20 mg also achieved statistically significant mean changes from baseline for the following secondary lipid and lipoprotein variables: HDL-C, TC, non-HDL-C, LDL-C/HDL-C, TC/HDL-C, TG/HDL-C, non-HDL C/HDL-C, ApoB, ApoB/ApoA-1. These changes were each in the direction of improved lipid responses and were sustained over 2 years.
No effect on growth or sexual maturation was detected after 24 months of treatment.
Pharmacokinetics: Rosuvastatin (ROSUKON-20) is administered orally in the active form with peak plasma levels occurring 5 hours after dosing. Exposure increases linearly over the dose range. The half life is 19 hours and does not increase with increasing dose. Absolute bioavailability is 20%. There is minimal accumulation on repeated once daily dosing.
Rosuvastatin undergoes first pass extraction in the liver, which is the primary site of cholesterol synthesis and LDL-C clearance.
Rosuvastatin is approximately 90% bound to plasma proteins, mostly albumin. The parent compound, accounts for greater than 90% of the circulating active HMG CoA reductase inhibitor activity.
Rosuvastatin undergoes limited metabolism (approximately 10%), mainly to the N-desmethyl form, and 90% is eliminated as unchanged drug in the faeces with the remainder being excreted in the urine.
Special populations: Age and sex: There was no clinically relevant effect of age or sex on the pharmacokinetics of rosuvastatin in adults. The exposure in children and adolescents with heterozygous familial hypercholesterolaemia appears to be similar to or lower than that in adult patients with dyslipidemia.
Race: Pharmacokinetic studies show an approximate 2-fold elevation in median AUC in Asian subjects compared with Caucasians. A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic and Black or Afro-Caribbean groups.
Renal insufficiency: In a study in subjects with varying degrees of renal impairment, mild to moderate renal disease had little influence on plasma concentrations of rosuvastatin. However, subjects with severe impairment (CrCl <30 ml/min) had a 3-fold increase in plasma concentration compared to healthy volunteers.
Hepatic insufficiency: In a study in subjects with varying degrees of hepatic impairment there was no evidence of increased exposure to rosuvastatin other than in the 2 subjects with the most severe liver disease (Child-Pugh scores of 8 and 9). In these subjects systemic exposure was increased by at least 2-fold compared to subjects with lower Child-Pugh scores.
Genetic polymorphisms: Disposition of HMG-CoA reductase inhibitors, including rosuvastatin, involves OATP1B1 and BCRP transporter proteins. In patients with SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) genetic polymorphisms there is a risk of increased rosuvastatin exposure. Individual polymorphisms of SLCO1B1 c.521CC and ABCG2 c.421AA are associated with an approximate 1.6-fold higher rosuvastatin exposure (AUC) or 2.4-fold higher exposure, respectively, compared to the SLCO1B1 c.521TT or ABCG2 c.421CC genotypes.
