Liprimar, 30 pcs., 20 mg, film-coated tablets


Liprimar, 30 pcs., 20 mg, film-coated tablets

Atorvastatin

- a selective competitive inhibitor of HMG-CoA reductase, a key enzyme that converts 3-hydroxy-3-methylglutaryl-CoA into mevalonate, a precursor of steroids, including cholesterol, a synthetic lipid-lowering agent.

In patients with homozygous and heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed dyslipidemia, atorvastatin reduces the plasma levels of total cholesterol (C), LDL-C and apolipoprotein B (apo-B), as well as VLDL-C and triglycerides (TG), causes an unstable increase in HDL-C levels.

Atorvastatin reduces the concentration of cholesterol and lipoproteins in the blood plasma by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and increasing the number of hepatic LDL receptors on the cell surface, which leads to increased uptake and catabolism of LDL-C.

Atorvastatin reduces the formation of LDL-C and the number of LDL particles, causes a pronounced and persistent increase in the activity of LDL receptors in combination with favorable qualitative changes in LDL particles, and also reduces the level of LDL-C in patients with homozygous hereditary familial hypercholesterolemia, resistant to therapy with other lipid-lowering drugs means.

Atorvastatin in doses from 10 to 80 mg reduces total cholesterol by 30–46%, LDL-C by 41–61%, apolipoprotein B by 34–50% and TG by 14–33%. The results of therapy are similar in patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed hyperlipidemia, incl. in patients with non-insulin-dependent diabetes mellitus.

In patients with isolated hypertriglyceridemia, atorvastatin reduces total cholesterol, LDL-C, VLDL-C, apo-B and TG and increases HDL-C levels.

In patients with dysbetalipoproteinemia, atorvastatin reduces the level of intermediate-density lipoprotein cholesterol.

In patients with Frederickson type IIa and IIb hyperlipoproteinemia, the mean increase in HDL-C levels during treatment with atorvastatin (10–80 mg) compared to baseline is 5.1–8.7% and is independent of dose. There is a significant dose-dependent decrease in the ratios: total cholesterol/HDL-C and LDL-C/HDL-C by 29–44% and 37–55%, respectively.

Liprimar® at a dose of 80 mg significantly reduces the risk of ischemic complications and mortality rate by 16% after a 16-week course, and the risk of re-hospitalization for angina pectoris accompanied by signs of myocardial ischemia by 26%. In patients with different initial concentrations of LDL-C, Liprimar® causes a reduction in the risk of ischemic complications and mortality (in patients with myocardial infarction without a Q wave and unstable angina, regardless of the patient’s gender and age).

A decrease in plasma LDL cholesterol levels correlates better with the dose of the drug than with its concentration in the blood plasma. The dose is selected taking into account the therapeutic effect (see section “Method of administration and dosage”).

The therapeutic effect is achieved 2 weeks after the start of therapy, reaches a maximum after 4 weeks and persists throughout the entire period of therapy.

Prevention of cardiovascular complications

In the Anglo-Scandinavian study of cardiovascular complications (lipid-lowering branch (ASCOT-LLA) of the effect of atorvastatin on fatal and non-fatal outcomes of coronary artery disease, it was found that the effect of treatment with atorvastatin at a dose of 10 mg significantly exceeded the effect of placebo, and therefore a decision was made to early ending the study after 3.3 years instead of the expected 5 years.

Atorvastatin significantly reduced the risk of developing the following complications (see Table 1).

Table 1

Cardiovascular complicationsRisk reduction, %
Coronary complications (fatal coronary artery disease and non-fatal myocardial infarction)36
Common cardiovascular complications and revascularization procedures20
Common cardiovascular complications29
Stroke (fatal and non-fatal)26

There were no significant reductions in overall mortality and mortality from cardiovascular causes, although positive trends were observed.

Diabetes

The pooled study of the effect of atorvastatin on fatal and nonfatal cardiovascular events in type 2 diabetes mellitus (CARDS) showed that treatment with atorvastatin reduced the risk of developing the following cardiovascular events, regardless of patient sex, age, or baseline LDL-C level (see Table 2).

table 2

ComplicationsRisk reduction, %
Major cardiovascular complications (fatal and nonfatal acute myocardial infarction, latent myocardial infarction, death due to exacerbation of coronary artery disease, unstable angina, coronary artery bypass grafting, subcutaneous transluminal coronary angioplasty, revascularization procedures, stroke)37
Myocardial infarction (fatal and non-fatal acute myocardial infarction, latent myocardial infarction)42
Stroke (fatal and non-fatal)48

Atherosclerosis

The Reversal of Coronary Atherosclerosis with Intensive Lipid-Lowering Therapy (REVERSAL) study with atorvastatin 80 mg in patients with coronary artery disease found that the mean reduction in total atheroma volume (the primary outcome measure) from the start of the study was 0.4%.

Recurrent stroke

The Intensive Lowering Cholesterol Levels (SPARCL) program found that atorvastatin 80 mg/day reduced the risk of recurrent fatal or nonfatal stroke in patients who had a stroke or transient ischemic attack (TIA) without a history of CAD by 15% compared with placebo. At the same time, the risk of major cardiovascular complications and revascularization procedures was significantly reduced. A reduction in the risk of cardiovascular events during atorvastatin therapy was observed in all groups except the one that included patients with primary or recurrent hemorrhagic stroke (7 in the atorvastatin group versus 2 in the placebo group).

Hemorrhagic stroke

In patients treated with atorvastatin 80 mg, the incidence of hemorrhagic or ischemic stroke (265 versus 311) or coronary artery disease (123 versus 204) was lower than in the control group.

Secondary prevention of cardiovascular complications

The New Targeted Trial (TNT) compared the effect of atorvastatin 80 and 10 mg/day on the risk of cardiovascular events in patients with clinically documented CAD. Atorvastatin at a dose of 80 mg significantly reduced the development of the following complications (see Table 3).

Table 3

ComplicationsAtorvastatin 80 mg
Primary endpoint
First major cardiovascular complication (fatal coronary artery disease and nonfatal myocardial infarction)8,7%
MI non-fatal, not related to the procedure4,9%
Stroke (fatal and non-fatal)2,3%
Secondary endpoint
First hospitalization for congestive heart failure2,4%
First coronary artery bypass graft or other revascularization procedures13,4%
First documented angina10,9%

Liprimar®

During treatment with HMG-CoA reductase inhibitors, with simultaneous use of cyclosporine, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day) or inhibitors of the CYP3A4 isoenzyme / transport protein (for example, erythromycin, clarithromycin, antifungal agents - azole derivatives), the risk increases myopathy (see section “Special instructions”).

CYP3A4 isoenzyme inhibitors

Since atorvastatin is metabolized by the CYP3A4 isoenzyme, co-administration of atorvastatin with inhibitors of the CYP3A4 isoenzyme may lead to increased plasma concentrations of atorvastatin. The degree of interaction and potentiation effect is determined by the variability of the effect on the CYP3A4 isoenzyme.

It was found that potent inhibitors of the CYP3A4 isoenzyme lead to a significant increase in the concentration of atorvastatin in the blood plasma. The simultaneous use of strong inhibitors of the CYP3A4 isoenzyme (for example, cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided whenever possible. . If concomitant use of these drugs is necessary, initiating therapy at the lowest dose should be considered and the possibility of reducing the maximum dose of atorvastatin should be evaluated.

Moderate inhibitors of the CYP3A4 isoenzyme (for example, erythromycin, diltiazem, verapamil and fluconazole) may lead to increased plasma concentrations of atorvastatin. With the simultaneous use of HMG-CoA reductase inhibitors (statins) and erythromycin, an increased risk of developing myopathy was noted. Interaction studies between amiodarone or verapamil and atorvastatin have not been conducted. Both amiodarone and verapamil are known to inhibit the activity of the CYP3A4 isoenzyme, and simultaneous use of these drugs with atorvastatin may lead to increased exposure to atorvastatin. In this regard, it is recommended to reduce the maximum dose of atorvastatin and carry out appropriate monitoring of the patient's condition when used simultaneously with moderate inhibitors of the CYP3A4 isoenzyme. Monitoring should be carried out after the start of therapy and against the background of changing the dose of the inhibitor.

Gemfibrozil/fibrates

With the use of fibrates in monotherapy, adverse reactions, including rhabdomyolysis, affecting the musculoskeletal system were periodically noted. The risk of such reactions increases with simultaneous use of fibrates and atorvastatin. If the simultaneous use of these drugs cannot be avoided, the minimum effective dose of atorvastatin should be used, and the patient's condition should be regularly monitored.

Ezetimibe

The use of ezetimibe is associated with the development of adverse reactions, including rhabdomyolysis, from the musculoskeletal system. The risk of such reactions increases with simultaneous use of ezetimibe and atorvastatin. For such patients, careful monitoring is recommended.

Erythromycin/clarithromycin

With the simultaneous use of atorvastatin and erythromycin (500 mg 4 times a day) or clarithromycin (500 mg 2 times a day), inhibitors of the CYP3A4 isoenzyme, an increase in the concentration of atorvastatin in the blood plasma was observed (see sections "Special instructions" and "Pharmacokinetics" ).

Protease inhibitors

The simultaneous use of atorvastatin with protease inhibitors, known as inhibitors of the CYP3A4 isoenzyme, is accompanied by an increase in the concentration of atorvastatin in the blood plasma.

Diltiazem

The combined use of atorvastatin at a dose of 40 mg with diltiazem at a dose of 240 mg leads to an increase in the concentration of atorvastatin in the blood plasma (see section “Pharmacokinetics”).

Cimetidine

No clinically significant interaction of atorvastatin with cimetidine was detected (see section “Pharmacokinetics”).

Itraconazole

The simultaneous use of atorvastatin in doses from 20 mg to 40 mg and itraconazole in a dose of 200 mg led to an increase in the AUC value of atorvastatin (see section "Pharmacokinetics").

Grapefruit juice

Since grapefruit juice contains one or more components that inhibit the CYP3A4 isoenzyme, its excessive consumption (more than 1.2 L per day) may cause an increase in the concentration of atorvastatin in the blood plasma (see section "Pharmacokinetics").

Transport protein inhibitors

Atorvastatin is a substrate of liver enzyme transporters (see section "Pharmacokinetics").

Co-administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in increased atorvastatin exposure (AUC ratio: 8.7) (see Pharmacokinetics section). Cyclosporine is an inhibitor of organic anion transport polypeptide 1B1 (OATP1B1), OATP1B3, multidrug resistance-associated protein 1 (MDR1) and breast cancer resistance protein, as well as CYP3A4, and therefore increases the exposure of atorvastatin. The daily dose of atorvastatin should not exceed 10 mg (see section “Dosage and Administration”).

Glecaprevir and pibrentasvir are inhibitors of OATP1B1, OATP1B3, MDR1 and breast cancer resistance protein, and therefore increase the exposure of atorvastatin. The daily dose of atorvastatin should not exceed 10 mg (see section “Dosage and Administration”).

Co-administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in increased atorvastatin exposure (AUC ratio: 3.29) (see Pharmacokinetics section).

Letermovir is an inhibitor of the transporters P-gp, BCRP, MRP2, OAT2 and the hepatic transporter OATP1B1/1B3, thus increasing the level of exposure to atorvastatin. The daily dose of atorvastatin should not exceed 20 mg (see section “Dosage and Administration”). The magnitude of indirect drug interactions between CYP3A and OATP1B1/1B3 on co-administration of drugs may differ when letermovir is co-administered with cyclosporine. It is not recommended to use atorvastatin in patients receiving letermovir therapy in combination with cyclosporine.

Elbasvir and grazoprevir are inhibitors of OATP1B1, OATP1B3, MDR1 and breast cancer resistance protein and therefore increase the exposure of atorvastatin. Should be used with caution and at the lowest dose required (see section "Dosage and Administration").

Inducers of the CYP3A4 isoenzyme

The combined use of atorvastatin with inducers of the CYP3A4 isoenzyme (for example, efavirenz, rifampicin or St. John's wort preparations) may lead to a decrease in the concentration of atorvastatin in the blood plasma. Due to the dual mechanism of interaction with rifampicin (an inducer of the CYP3A4 isoenzyme and an inhibitor of the hepatocyte transport protein OATP1B1), simultaneous use of atorvastatin and rifampicin is recommended, since delayed administration of atorvastatin after taking rifampicin leads to a significant decrease in the concentration of atorvastatin in the blood plasma (see section “Pharmacokinetics”). However, the effect of rifampicin on the concentration of atorvastatin in hepatocytes is unknown and if concomitant use cannot be avoided, the effectiveness of this combination should be carefully monitored during therapy.

Antacids

Simultaneous oral administration of a suspension containing magnesium hydroxide and aluminum hydroxide reduced the concentration of atorvastatin in the blood plasma (change in AUC: 0.66), but the degree of reduction in the concentration of LDL-C did not change.

Phenazone

Atorvastatin does not affect the pharmacokinetics of phenazone, so interaction with other drugs metabolized by the same cytochrome isoenzymes is not expected.

Colestipol

With simultaneous use of colestipol, the concentration of atorvastatin in the blood plasma decreased (change in AUC: 0.74); however, the lipid-lowering effect of the combination of atorvastatin and colestipol was superior to that of each drug alone.

Digoxin

With repeated administration of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentrations of digoxin in the blood plasma did not change. However, when digoxin was used in combination with atorvastatin at a dose of 80 mg/day, digoxin concentrations increased (AUC change: 1.15). Patients receiving digoxin in combination with atorvastatin require appropriate monitoring.

Azithromycin

With simultaneous use of atorvastatin at a dose of 10 mg 1 time per day and azithromycin at a dose of 500 mg 1 time per day, the concentration of atorvastatin in the blood plasma did not change.

Oral contraceptives

With simultaneous use of atorvastatin and oral contraceptives containing norethisterone and ethinyl estradiol, increased concentrations of norethisterone (AUC change 1.28) and ethinyl estradiol (AUC change 1.19) were observed. This effect should be taken into account when choosing an oral contraceptive for a woman taking atorvastatin.

Terfenadine

With simultaneous use of atorvastatin and terfenadine, no clinically significant changes in the pharmacokinetics of terfenadine were detected.

Warfarin

In a clinical study in patients regularly receiving warfarin therapy, concomitant use of atorvastatin at a dose of 80 mg per day resulted in a slight increase in prothrombin time of approximately 1.7 s during the first 4 days of therapy. The indicator returned to normal within 15 days of atorvastatin therapy.

Although significant interactions affecting anticoagulant function have been observed only in rare cases, the prothrombin time should be determined before initiating atorvastatin therapy in patients receiving coumarin anticoagulant therapy and frequently enough during therapy to prevent a significant change in the prothrombin time. Once stable prothrombin time values ​​are observed, its monitoring can be carried out in the same way as recommended for patients receiving coumarin anticoagulants.

When changing the dose of atorvastatin or discontinuing therapy, prothrombin time should be monitored according to the same principles as described above.

Atorvastatin therapy was not associated with bleeding or changes in prothrombin time in patients not receiving anticoagulant treatment.

Colchicine

Although studies have not been conducted on the simultaneous use of colchicine and atorvastatin, there are reports of the development of myopathy when using this combination. Caution should be exercised when atorvastatin and colchicine are used concomitantly.

Amlodipine

In a drug interaction study in healthy subjects, coadministration of atorvastatin 80 mg and amlodipine 10 mg resulted in a clinically nonsignificant increase in atorvastatin concentrations (AUC change: 1.18)

Fusidic acid

During post-marketing studies, cases of rhabdomyolysis have been reported in patients taking concomitant statins, including atorvastatin and fusidic acid. The mechanism of this interaction is unknown. In patients for whom the use of fusidic acid is considered necessary, statin treatment should be discontinued for the entire period of use of fusidic acid. Statin therapy can be resumed 7 days after the last dose of fusidic acid. In exceptional cases where long-term systemic therapy with fusidic acid is necessary, for example for the treatment of severe infections, the need for co-administration of atorvastatin and fusidic acid should be considered on a case-by-case basis and under close medical supervision. The patient should seek immediate medical attention if symptoms of muscle weakness, tenderness, or pain occur.

Other concomitant therapy

In clinical studies, atorvastatin was used in combination with antihypertensive agents and estrogens as part of hormone replacement therapy. There were no signs of clinically significant adverse interactions; No interaction studies with specific drugs have been conducted.

In addition, an increase in the concentration of atorvastatin was observed when used simultaneously with HIV protease inhibitors (combinations of lopinavir and ritonavir, saquinavir and ritonavir, darunavir and ritonavir, fosamprenavir, fosamprenavir with ritonavir and nelfinavir), hepatitis C protease inhibitors (boceprevir, elbasvir/grazoprevir, simeprevir) , clarithromycin and itraconazole.

Caution should be exercised when using these drugs together and the lowest effective dose of atorvastatin should be used.

Liprimar

Synthetic lipid-lowering drug. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, a key enzyme that converts 3-hydroxy-3-methylglutaryl-CoA into mevalonate, a precursor of steroids, including cholesterol.

In patients with homozygous and heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed dyslipidemia, atorvastatin reduces the content of total cholesterol (C), LDL-C and apolipoprotein B (apo-B) in the blood plasma, as well as the content of VLDL-C and TG, causing unstable increase in HDL-C levels.

Atorvastatin reduces the concentration of cholesterol and lipoproteins in the blood plasma by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and increasing the number of hepatic LDL receptors on the cell surface, which leads to increased uptake and catabolism of LDL-C.

Atorvastatin reduces the formation of LDL-C and the number of LDL particles. Causes a pronounced and persistent increase in the activity of LDL receptors, combined with favorable qualitative changes in LDL particles. Reduces the level of LDL-C in patients with homozygous hereditary hypercholesterolemia, resistant to therapy with other lipid-lowering drugs.

Atorvastatin in doses of 10-80 mg reduces total cholesterol by 30-46%, LDL-C by 41-61%, apo-B by 34-50% and TG by 14-33%. Treatment results are similar in patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed hyperlipidemia, incl. in patients with non-insulin-dependent diabetes mellitus.

In patients with isolated hypertriglyceridemia, atorvastatin reduces the levels of total cholesterol, LDL-C, VLDL-C, apo-B and TG and increases the level of HDL-C. In patients with dysbetalipoproteinemia, it reduces the level of intermediate-density lipoprotein cholesterol.

In patients with hyperlipoproteinemia types IIa and IIb according to the Fredrickson classification, the average increase in HDL-C levels during treatment with atorvastatin (10-80 mg), compared with the baseline value, is 5.1-8.7% and is independent of dose. There is a significant dose-dependent decrease in the ratios: total cholesterol/HDL-C and LDL-C/HDL-C by 29-44% and 37-55%, respectively.

Liprimar® at a dose of 80 mg significantly reduces the risk of ischemic complications and mortality rate by 16% after a 16-week course, and the risk of re-hospitalization for angina pectoris accompanied by signs of myocardial ischemia by 26%. In patients with different initial levels of LDL-C, Liprimar® causes a reduction in the risk of ischemic complications and death (in patients with myocardial infarction without a Q wave and unstable angina, men and women, patients under and over 65 years of age).

A decrease in plasma LDL cholesterol levels correlates better with the dose of the drug than with its concentration in the blood plasma.

The therapeutic effect is achieved 2 weeks after the start of therapy, reaches a maximum after 4 weeks and persists throughout the entire period of therapy.

Prevention of cardiovascular diseases

In the Anglo-Scandinavian study of cardiovascular complications, lipid-lowering branch (ASCOT-LLA), the effect of atorvastatin on fatal and non-fatal outcomes of coronary artery disease found that the effect of treatment with atorvastatin at a dose of 10 mg significantly exceeded the effect of placebo, and therefore it was decided to early termination of the study after 3.3 years instead of the expected 5 years.

Atorvastatin significantly reduced the development of the following complications:

ComplicationsRisk reduction
Coronary complications (fatal coronary artery disease and non-fatal myocardial infarction)36%
Common cardiovascular complications and revascularization procedures20%
Common cardiovascular complications29%
Stroke (fatal and non-fatal)26%

There were no significant reductions in overall mortality and mortality from cardiovascular causes, although positive trends were observed.

Diabetes

The pooled study of the effects of atorvastatin in patients with type 2 diabetes (CARDS) on fatal and non-fatal cardiovascular disease outcomes showed that atorvastatin therapy, regardless of patient gender, age or baseline LDL-C level, reduced the risk of developing the following cardiovascular events :

ComplicationsRisk reduction
Major cardiovascular complications (fatal and nonfatal acute myocardial infarction, latent myocardial infarction, death due to exacerbation of coronary artery disease, unstable angina, coronary artery bypass grafting, subcutaneous transluminal coronary angioplasty, revascularization, stroke)37%
Myocardial infarction (fatal and non-fatal acute myocardial infarction, latent myocardial infarction)42%
Stroke (fatal and non-fatal)48%

Atherosclerosis

The Reversal of Coronary Atherosclerosis with Intensive Lipid-Lowering Therapy (REVERSAL) study with atorvastatin 80 mg in patients with coronary artery disease found that the average reduction in total atheroma volume (the primary outcome measure) from the start of the study was 0.4%.

Recurrent stroke

The Intensive Reduction in Cholesterol Levels (SPARCL) program found that atorvastatin 80 mg/day reduced the risk of recurrent fatal or nonfatal stroke in patients with a history of stroke or transient ischemic attack without a history of coronary artery disease by 15% compared with placebo. At the same time, the risk of major cardiovascular complications and revascularization procedures was significantly reduced. A reduction in the risk of cardiovascular events during atorvastatin therapy was observed in all groups except the one that included patients with primary or recurrent hemorrhagic stroke (7 in the atorvastatin group versus 2 in the placebo group).

Hemorrhagic stroke

In patients treated with atorvastatin 80 mg, the incidence of hemorrhagic or ischemic stroke (265 versus 311) or coronary artery disease (123 versus 204) was lower than in the control group.

Secondary prevention of cardiovascular complications

The Treatment of the New Targeted Trial (TNT) compared the effect of atorvastatin at doses of 80 mg/day and 10 mg/day on the risk of cardiovascular events in patients with clinically confirmed coronary artery disease.

Atorvastatin at a dose of 80 mg significantly reduced the development of the following complications:

ComplicationsAtorvastatin 80 mg
Primary endpoint
First major cardiovascular complication (fatal coronary artery disease and nonfatal myocardial infarction)8.7%
Myocardial infarction, non-fatal, not related to the procedure4.9%
Stroke (fatal and non-fatal)2.3%
Secondary endpoint
First hospitalization for congestive heart failure2.4%
First coronary artery bypass graft or other revascularization procedures13.4%
First documented angina10.9%

Pharmacokinetics

Suction

Atorvastatin is rapidly absorbed after oral administration; Cmax is reached after 1-2 hours. The degree of absorption and plasma concentrations of atorvastatin increase in proportion to the dose. The absolute bioavailability of atorvastatin is about 14%, and the systemic bioavailability of HMG-CoA reductase inhibitory activity is about 30%. Low systemic bioavailability is due to first-pass metabolism in the gastrointestinal mucosa and/or during the “first pass” through the liver. Food reduces the rate and extent of absorption by approximately 25% and 9%, respectively (as evidenced by Cmax and AUC), but the reduction in LDL-C is similar to that observed with fasting atorvastatin. Despite the fact that after taking atorvastatin in the evening, its plasma concentration is lower (Cmax and AUC by approximately 30%) than after taking it in the morning, the decrease in LDL-C does not depend on the time of day at which the drug is taken.

Distribution

The average Vd of atorvastatin is about 381 l. The binding of atorvastatin to plasma proteins is at least 98%. The ratio of atorvastatin content in red blood cells/blood plasma is about 0.25, i.e. Atorvastatin penetrates red blood cells poorly.

Metabolism

Atorvastatin is extensively metabolized to form ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro, ortho- and parahydroxylated metabolites have an inhibitory effect on HMG-CoA reductase comparable to that of atorvastatin. Approximately 70% of the decrease in HMG-CoA reductase activity is due to the activity of circulating metabolites. The results of in vitro studies suggest that the CYP3A4 isoenzyme plays an important role in the metabolism of atorvastatin. This is confirmed by an increase in the concentration of atorvastatin in human plasma while taking erythromycin, which is an inhibitor of this isoenzyme. In vitro studies have also shown that atorvastatin is a weak inhibitor of the CYP3A4 isoenzyme. Atorvastatin does not have a clinically significant effect on the plasma concentration of terfenadine, which is metabolized mainly by the CYP3A4 isoenzyme; therefore, a significant effect of atorvastatin on the pharmacokinetics of other substrates of the CYP3A4 isoenzyme is unlikely.

Removal

Atorvastatin and its metabolites are excreted mainly in bile after hepatic and/or extrahepatic metabolism (atorvastatin does not undergo significant enterohepatic recirculation). T1/2 is about 14 hours, while the inhibitory effect of the drug on HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites and persists for about 20-30 hours due to their presence. After oral administration, less than 2% of the atorvastatin dose is found in the urine.

Pharmacokinetics in special clinical situations

Plasma concentrations of atorvastatin in patients over 65 years of age are higher (Cmax approximately 40%, AUC approximately 30%) than in younger adult patients. There were no differences in the safety, effectiveness, or achievement of lipid-lowering treatment goals in elderly patients compared with the general population.

Pharmacokinetic studies of the drug have not been conducted in children.

Plasma concentrations of atorvastatin in women differ (Cmax is approximately 20% higher and AUC is 10% lower) from those in men.

Impaired renal function does not affect the plasma concentration of atorvastatin or its effect on lipid metabolism. In this regard, no dose changes are required in patients with impaired renal function.

Atorvastatin is not excreted during hemodialysis due to intense binding to plasma proteins.

Atorvastatin concentrations are significantly increased (Cmax and AUC approximately 16-fold and 11-fold, respectively) in patients with alcoholic cirrhosis (Child-Pugh class B).

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