Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: HMG-CoA reductase inhibitors in combination with other lipid modifying agents, rosuvastatin and ezetimibe
ATC code: C10BA06

Mechanism of action:
Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Rosetemib S.K contains rosuvastatin and ezetimibe, two lipid-lowering compounds with complementary mechanisms of action. Rosetemib S.K reduces elevated total cholesterol (total-C), LDL-C, apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non- HDL-C), and increases high-density lipoprotein cholesterol (HDL-C) through dual inhibition of cholesterol synthesis and absorption.

Ezetimibe

Mechanism of action
Ezetimibe inhibits the intestinal absorption of cholesterol and related plant sterols. Ezetimibe is orally active, and has a mechanism of action that differs from other classes of cholesterol- reducing compounds (e.g. statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols.

Ezetimibe localises at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver; statins reduce cholesterol synthesis in the liver and together these distinct mechanisms provide complementary cholesterol reduction. In a 2-week clinical study in 18 hypercholesterolaemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo.

Pharmacodynamic effects
A series of preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [14C]-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or fat soluble vitamins A and D.

Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C.

Administration of ezetimibe with a statin is effective in reducing the risk of cardiovascular events in patients with coronary heart disease and ACS event history.

Clinical efficacy and safety
In controlled clinical studies, ezetimibe, either as monotherapy or co-administered with a statin significantly reduced total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG) and increased high-density lipoprotein cholesterol (HDL-C) in patients with hypercholesterolaemia.

Primary hypercholesterolaemia
In a double-blind, placebo-controlled, 8-week study, 769 patients with hypercholesterolaemia already receiving statin monotherapy and not at National Cholesterol Education Program (NCEP) LDL-C goal (2.6 to 4.1 mmol/l [100 to 160 mg/dl], depending on baseline characteristics) were randomised to receive either ezetimibe 10 mg or placebo in addition to their on-going statin therapy.

Among statin-treated patients not at LDL-C goal at baseline (~82%), significantly more patients randomised to ezetimibe achieved their LDL-C goal at study endpoint compared to patients randomised to placebo, 72% and 19%, respectively. The corresponding LDL-C reductions were significantly different (25% and 4% for ezetimibe versus placebo, respectively). In addition, ezetimibe, added to on-going statin therapy, significantly decreased total-C, Apo B, TG and increased HDL-C, compared with placebo. Ezetimibe or placebo added to statin therapy reduced median C-reactive protein by 10% or 0% from baseline, respectively.

In two, double-blind, randomised placebo-controlled, 12-week studies in 1,719 patients with primary hypercholesterolaemia, ezetimibe 10 mg significantly lowered total-C (13%), LDL-C (19%), Apo B (14%), and TG (8%) and increased HDL-C (3%) compared to placebo. In addition, ezetimibe had no effect on the plasma concentrations of fat-soluble vitamins A, D, and E, no effect on prothrombin time, and, like other lipid-lowering agents, did not impair adrenocortical steroid hormone production.

Rosuvastatin

Mechanism of action
Rosuvastatin 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 for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering.

Rosuvastatin 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.

Pharmacodynamic effects
Rosuvastatin 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 Table 2). Rosuvastatin also lowers the LDL-C/HDL-C, total C/HDL-C and nonHDL- C/HDL-C and the ApoB/ApoA-I ratios.
Table 2: Dose response in patients with primary hypercholesterolaemia (type IIa and IIb) (adjusted mean percent change from baseline)
Dose        N     LDL-C       Total-C      HDL-C       TG    nonHDL-C         ApoB      ApoA-I Placebo     13    -7          -5           3           -3    -7               -3        0 5          17    -45         -33          13          -35   -44              -38       4 10          17    -52         -36          14          -10   -48              -42       4 20          17    -55         -40          8           -23   -51              -46       5
40          18    -63         -46          10          -28   -60              -54       0

A therapeutic effect is obtained within 1 week following treatment initiation and 90% of maximum response is achieved in 2 weeks. The maximum response is usually achieved by 4 weeks and is maintained after that.

Clinical efficacy and safety
Rosuvastatin is effective in adults with hypercholesterolaemia, with and without hypertriglyceridaemia, regardless of race, sex, or age and in special populations such as diabetics, or patients with familial hypercholesterolaemia.

From pooled phase III data, rosuvastatin has been shown to be effective at treating the majority of patients with type IIa and IIb hypercholesterolaemia (mean baseline LDL-C about 4.8 mmol/l) to recognised European Atherosclerosis Society (EAS; 1998) guideline targets; about 80% of patients treated with 10 mg reached the EAS targets for LDL-C levels (<3 mmol/l).

In a large study, 435 patients with heterozygous familial hypercholesterolaemia were given rosuvastatin from 20 mg to 80 mg in a force-titration design. All doses showed a beneficial effect on lipid parameters and treatment to target goals. Following titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C was reduced by 53%. 33% of patients reached EAS guidelines for LDL-C levels (<3 mmol/l).

In a force-titration, open label trial, 42 patients with homozygous familial hypercholesterolaemia were evaluated for their response to rosuvastatin 20-40 mg. In the overall population, the mean LDL-C reduction was 22%.

Rosuvastatin/ezetimibe combination

Clinical efficacy and safety
Combination rosuvastatin with ezetimibe 10 mg enabled greater decreases in LDL cholesterol and allowed more patients to achieve LDL cholesterol goals. This has been demonstrated in a clinical study with 469 patients, who were randomly assigned to rosuvastatin alone or in combination with ezetimibe for 6 weeks.

The combination of rosuvastatin/ezetimibe reduced LDL cholesterol significantly more than rosuvastatin (3.4 mmol/l vs. 2.8 mmol/l). Other components of the lipid/lipoprotein profile were also significantly (p < 0.001) improved with rosuvastatin/ezetimibe. Both treatments generally were well tolerated.

Another 6-week, randomized, double-blind, parallel-group, clinical trial evaluated the safety and efficacy of ezetimibe (10 mg) added to stable rosuvastatin therapy versus up-titration of rosuvastatin from 5 to 10 mg or from 10 to 20 mg.

The study population included 440 subjects at moderately high/high risk of coronary heart disease with low-density lipoprotein (LDL) cholesterol levels higher than the National Cholesterol Education Program Adult Treatment Panel III recommendations (<100 mg/dl for moderately high/high-risk subjects without atherosclerotic vascular disease or <70 mg/dl for high-risk subjects with atherosclerotic vascular disease). Pooled data demonstrated that ezetimibe added to stable rosuvastatin 5 mg or 10 mg reduced LDL cholesterol by 21%. In contrast, doubling rosuvastatin to 10 mg or 20 mg reduced LDL cholesterol by 5.7%. Individually, ezetimibe plus rosuvastatin 5 mg reduced LDL cholesterol more than did rosuvastatin 10 mg, and ezetimibe plus rosuvastatin 10 mg reduced LDL cholesterol more than did rosuvastatin 20 mg. Compared to rosuvastatin up-titration, ezetimibe add-on achieved significantly greater attainment of LDL cholesterol levels of <70 or <100 mg/dl, and <70 mg/dl in all subjects; produced significantly greater reductions in total cholesterol, non–high-density lipoprotein cholesterol, and apolipoprotein B; and resulted in similar effects on other lipid parameters. In conclusion, compared to up-titration doubling of the rosuvastatin dose, ezetimibe 10 mg added to stable rosuvastatin 5 mg or 10 mg produced greater improvements in many lipid parameters.
A multi-center, randomized, double blind, double-dummy, parallel arms, active-controlled study (LPS15021) was conducted in 452 patients with primary hypercholesterolaemia and at high risk (HR) or very high risk (VHR) for cardiovascular disease (CVD) and who are not adequately controlled with a 10 mg or 20 mg stable daily dose of rosuvastatin or equipotent statin, without any other lipid-modifying therapy (LMT).

During the 6-week double-blind treatment phase:

-       208 patients with HR were randomized to receive rosuvastatin 10 mg plus ezetimibe 10 mg as fixed dose combination (FDC) (R10/E10, n=104) or rosuvastatin 20 mg (R20, n=104).
-       244 patients with VHR were randomized to receive rosuvastatin 20 mg plus ezetimibe 10 mg as FDC (R20/E10, n=82) or rosuvastatin 40 mg plus ezetimibe 10 mg as FDC (R40/E10, n=79) or rosuvastatin 40 mg (R40, n=83).

The primary endpoint was the percent change in calculated LDL-C, from baseline to Week 6 in the modified intent-to-treat (mITT) population.

In the VHR stratum, the LS (least squares) mean change in LDL-C from baseline to Week 6 was -34.28% for the R40/E10 group, -26.90% for the R20/E10 group and -14.62% for the R40 group.
Superiority of FDC (R40/E10 or R20/E10) over R40 was demonstrated with LS mean differences of -19.66% (p <0.001) and -12.28% (p=0.015), respectively.

In the HR stratum, greater reduction in LDL-C from baseline to Week 6 was also observed for the FDC: LS mean changes of -27.02% for the R10/E10 group and -21.82% for the R20 group. A clinically relevant decrease in LDL-C for R10/E10 arm was observed, even though statistically superiority of R10/E10 versus R20 could not be demonstrated (LS mean difference of -5.20%; p=0.306).

After exclusion of data from one outlier participant in the R10/E10 arm, the difference in LDL-C percent change between treatment arms was statistically significant in the HR stratum (LS mean difference: R10/E10 versus R20: -8.84%; p=0.026).

Overall safety findings observed in patients treated with all three strengths of Rosetemib S.K were in line with known safety profile of rosuvastatin and ezetimibe.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

There is no substantial pharmacokinetic interaction between the two components of this fixed- dose preparation.
Mean AUC and Cmax values for total rosuvastatin and ezetimibe were not different between the monotherapy and coadministration groups of rosuvastatin 10 mg and ezetimibe 10 mg.

Absorption

Ezetimibe
After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a pharmacologically-active phenolic glucuronide (ezetimibe-glucuronide). Mean maximum plasma concentrations (Cmax) occur within 1 to 2 hours for ezetimibe-glucuronide and 4 to 12 hours for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection.

Concomitant food administration (high fat or non-fat meals) had no effect on the oral bioavailability of ezetimibe when administered as ezetimibe 10-mg tablets. Ezetimibe can be administered with or without food.

Rosuvastatin
Maximum rosuvastatin plasma concentrations are achieved approximately 5 hours after oral administration. The absolute bioavailability is approximately 20%.

Distribution

Ezetimibe
Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88 to 92% to human plasma proteins, respectively.

Rosuvastatin
Rosuvastatin is taken up extensively by the liver which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L.
Approximately 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.

Biotransformation

Ezetimibe
Ezetimibe is metabolised primarily in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20 % and 80 to 90 % of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with evidence of significant enterohepatic recycling. The half-life for ezetimibe and ezetimibe-glucuronide is approximately 22 hours.

Rosuvastatin
Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for cytochrome P450-based metabolism. CYP2C9 was the principal isoenzyme involved, with 2C19, 3A4 and 2D6 involved to a lesser extent. The main metabolites identified are the N-desmethyl and lactone metabolites.
The N-desmethyl metabolite is approximately 50% less active than rosuvastatin whereas the lactone form is considered clinically inactive. Rosuvastatin accounts for greater than 90% of the circulating HMG-CoA reductase inhibitor activity.

Elimination

Ezetimibe
Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe accounted for approximately 93% of the total radioactivity in plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the faeces and urine, respectively, over a 10-day collection period. After 48 hours, there were no detectable levels of radioactivity in the plasma.

Rosuvastatin
Approximately 90% of the rosuvastatin dose is excreted unchanged in the faeces (consisting of absorbed and non-absorbed active substance) and the remaining part is excreted in urine.
Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours. The elimination half-life does not increase at higher doses. The geometric mean plasma clearance is approximately 50 litres/hour (coefficient of variation 21.7%).
As with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter is important in the hepatic elimination of rosuvastatin.

Linearity: Systemic exposure of rosuvastatin increases in proportion to dose. There are no changes in pharmacokinetic parameters following multiple daily doses.

Special populations:

Hepatic impairment
Ezetimibe
After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child Pugh score 5 or 6), compared to healthy subjects. In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment (Child Pugh score 7 to 9), the mean AUC for total ezetimibe was increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. No dosage adjustment is necessary for patients with mild hepatic impairment. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe (Child Pugh score>9) hepatic impairment, ezetimibe is not recommended in these patients (see section 4.4).

Rosuvastatin
In a study with subjects with varying degrees of hepatic impairment there was no evidence of increased exposure to rosuvastatin in subjects with Child-Pugh scores of 7 or below. However, two subjects with Child-Pugh scores of 8 and 9 showed an increase in systemic exposure of at least 2-fold compared to subjects with lower Child-Pugh scores. There is no experience in subjects with Child-Pugh scores above 9.

Renal impairment

Ezetimibe
After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl 30 ml/min/1.73m2), the mean AUC for total ezetimibe was increased approximately 1.5-fold, compared to healthy subjects (n=9). This result is not considered clinically significant. No dosage adjustment is necessary for renally impaired patients.

An additional patient in this study (post-renal transplant and receiving multiple medications, including ciclosporin) had a 12-fold greater exposure to total ezetimibe.

Rosuvastatin
In a study in subjects with varying degrees of renal impairment, mild to moderate renal disease had no influence on plasma concentration of rosuvastatin or the N-desmethyl metabolite. Subjects with severe impairment (CrCl <30 ml/min) had a 3-fold increase in plasma concentration and a 9- fold increase in the N-desmethyl metabolite concentration compared to healthy volunteers.
Steady-state plasma concentrations of rosuvastatin in subjects undergoing haemodialysis were approximately 50% greater compared to healthy volunteers.
Age and gender

Ezetimibe
Plasma concentrations for total ezetimibe are about 2 - fold higher in the elderly ( 65 years) than in the young (18 to 45 years). LDL-C reduction and safety profile are comparable between elderly and young subjects treated with ezetimibe. Therefore, no dosage adjustment is necessary in the elderly.

Plasma concentrations for total ezetimibe are slightly higher (approximately 20%) in women than in men. LDL-C reduction and safety profile are comparable between men and women treated with ezetimibe. Therefore, no dosage adjustment is necessary on the basis of gender.

Rosuvastatin
There was no clinically relevant effect of age or sex on the pharmacokinetics of rosuvastatin in adults.

Paediatric population

Ezetimibe
The pharmacokinetics of ezetimibe are similar between children ≥6 years and adults.
Pharmacokinetic data in the paediatric population <6 years of age are not available. Clinical experience in paediatric and adolescent patients includes patients with HoFH, HeFH, or sitosterolaemia.

Rosuvastatin
Two pharmacokinetic studies with rosuvastatin (given as tablets) in paediatric patients with heterozygous familial hypercholesterolaemia 10-17 or 6-17 years of age (total of 214 patients) demonstrated that exposure in paediatric patients appears comparable to or lower than that in adult patients. Rosuvastatin exposure was predictable with respect to dose and time over a 2-year period.

Race

Rosuvastatin
Pharmacokinetic studies show an approximate 2-fold elevation in median AUC and Cmax in Asian subjects (Japanese, Chinese, Filipino, Vietnamese and Koreans) compared with Caucasians.
Asian-Indians show an approximate 1.3-fold elevation in median AUC and Cmax. A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics between Caucasian and Black groups.

Genetic polymorphisms

Rosuvastatin
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 a higher rosuvastatin exposure (AUC) compared to the SLCO1B1 c.521TT or ABCG2 c.421CC genotypes. This specific genotyping is not established in clinical practice, but for patients who are known to have these types of polymorphisms, a lower daily dose of rosuvastatin is recommended.