Actions of Livazo 2mg in details
Pharmacology: Livazo 2mg calcium inhibits HMG-CoA reductase, which is a rate-determining enzyme involved with biosynthesis of cholesterol, in a manner of competition with the substrate so that it inhibits cholesterol synthesis in the liver. As a result, the expression of LDL-receptors followed by the uptake of LDL from blood to liver is accelerated and then the plasma total cholesterol decreases. Further, the sustained inhibition of cholesterol synthesis in the liver decreases VLDL secretion into blood, thus plasma triglyceride levels decrease.
Inhibition of HMG-CoA Reductase: Livazo 2mg calcium antagonistically inhibited HMG-CoA reductase in a study by using rat hepatic microsomes, the IC50 was 6.8 nM (in vitro).
Inhibition of Cholesterol Synthesis: Livazo 2mg calcium inhibited cholesterol synthesis dose-dependently in a study by using human liver cancer derived cells (HepG2) (in vitro). Moreover, liver-selective inhibition of cholesterol synthesis in case of oral administration was observed (rats).
Plasma Lipid Lowering Effect: Plasma total cholesterol and plasma triglycerides were significantly decreased by oral administration of Livazo 2mg calcium (dogs, guinea pigs).
Suppressing Effects on Lipid Accumulation and Intimal Thickening: Livazo 2mg calcium suppressed the accumulation of cholesteryl ester in macrophages loaded by oxidized-LDL (murine monocyte derived cell line) in vitro. Further, it significantly suppressed the intimal thickening in a model rabbit with a balloon-injured carotid artery through oral administration (rabbit).
Mechanism of Action: Acceleration of LDL-Receptor Expression: Livazo 2mg calcium accelerated the expression of mRNA for LDL-receptor in HepG2 cells so that the binding and the uptake of LDL and the apoB-degradation were increased (in vitro). Moreover, it accelerated LDL-receptor expression dose-dependently by oral administration (guinea pigs).
VLDL-Secretion Lowering Effect: The secretion of VLDL-triglyceride was significantly decreased by the oral administration of Livazo 2mg calcium (guinea pigs).
Pharmacokinetics: Pharmacokinetics in Adult Male Human Subjects: Plasma concentration after single dose oral administration: In 6 healthy adult male humans, single dose oral administration of Livazo 2mg calcium (2 mg or 4 mg) was performed under fasted conditions. Unchanged Livazo 2mg and its lactone, the main metabolite, were mainly found in plasma. The pharmacokinetic parameters after the administration of Livazo 2mg calcium (2 mg) is shown in the table as follows.
Effect of Food: Single oral dose administration demonstrated a delay in Tmax and a decrease in Cmax, but no significant difference in AUC.
Blood Concentration After RepeatedOral Administration:
After repeated oral administration of Livazo 2mg calcium 4 mg once a day, after breakfast for 7 days in 6 healthy adult human males, fluctuation of the pharmacokinetic parameters by repeated administration was slight and T½ was around 11 hrs.
Furthermore, after a 5-day repeated oral administration of Livazo 2mg calcium 2 mg once a day in 6 elderly subjects and 5 non-elderly subjects, no significant difference in the pharmacokinetic parameters in either cohort was observed.
Blood Concentration by Co-administration with Cyclosporin: Six-day repeated oral administration of Livazo 2mg calcium 2 mg in 6 healthy adult male subjects was performed with the administration of cyclosporin 2 mg/kg 1 hr before the administration of Livazo 2mg calcium on day 6. The plasma concentration of the unchanged Livazo 2mg increased by 6.6 times based on Cmax and by 4.6 times based on AUC compared to the control value.
Plasma Concentration by Co-administration with Fibrates (Data from Foreign Subjects): In 24 healthy adult humans, 6-day repeated oral administration of Livazo 2mg calcium 4 mg was performed followed by 1-day washout and then 7-day repeated oral co-administration of Livazo 2mg calcium 4 mg and fenofibrate or gemfibrozil. The plasma concentrations on the unchanged Livazo 2mg (AUC) increased by 1.2 times in fenofibrate and 1.4 times in gemfibrozil.
Pharmacokinetics in Hepatic Dysfunction: Cirrhosis (Data from Foreign Subjects): Single oral administration of Livazo 2mg calcium 2 mg in 12 patients with cirrhosis and 6 healthy volunteers was performed. The plasma concentration in the patients classified as Child-Pugh class A increased by 1.3 times based on Cmax and by 1.6 times based on AUC compared with normal hepatic function and that in Child-Pugh class B increased by 2.7 times based on Cmax and by 3.9 times based on AUC.
Fatty Liver Disease: Seven-day repeated oral administration of Livazo 2mg calcium 2 mg was performed in 6 patients with fatty liver and 6 subjects with normal hepatic function. The effect on the pharmacokinetics was minimal.
Urinary Excretion: After single oral administration of Livazo 2mg calcium 2 mg or 4 mg in 6 healthy adult male humans, the urinary excretion rate of the unchanged Livazo 2mg was <0.6%, and that of its lactone metabolite was <1.3%. The total excretion rate of the unchanged Livazo 2mg and its lactone was <2% of the dose.
After 7-day repeated oral dose of Livazo 2mg 4 mg once a day in 6 healthy adult human males, the urinary excretion of the unchanged Livazo 2mg and its lactone metabolite showed no increase during the period from the first administration until day 7 and decreased rapidly after completion of administration.
Metabolism: Livazo 2mg calcium was metabolized by cyclization to its lactone, β-oxidation on the side-chain, hydroxylation of the quinoline ring and glucuronate or taurine conjugation. The main route of excretion was rectally (rats, dogs).
In humans, the unchanged Livazo 2mg and its lactone metabolite as the main metabolite were mainly observed in blood and the other metabolites eg, propionate derivative and 8-hydroxide were minimally observed. Meanwhile, the unchanged Livazo 2mg, its lactone, dehydro-lactone, 8-hydroxide and these conjugates were minimally observed in urine.
Drug-Metabolizing Enzymes: Livazo 2mg calcium was minimally metabolized in study using human hepatic microsomes and the 8-hydroxide occurred mainly by CYP2C9 metabolism (in vitro).
An inhibitory study against model substrate of CYP species demonstrated that Livazo 2mg calcium did not affect the metabolism of tolbutamide, a substrate for CYP2C9 and testosterone, a substrate for CYP3A4 (in vitro).
Plasma Protein Binding Rate: Plasma protein binding rate of Livazo 2mg calcium was as high as 99.5-99.6% with 4% human serum albumin and 94.3-94.9% with 0.06% human α1-acid glycoprotein (in vitro).
Clinical Studies: The aggregated result of clinical studies (including a double-blind comparative study) by the administration of Livazo 2mg (1-4 mg) once a day for 8-104 weeks in 862 patients with hypercholesterolemia including familial hypercholesterolemia, showed a significant effect on serum lipids improvement. On week 8, the decline of total cholesterol was 28%, that of LDL-cholesterol was 40%, and that of triglyceride was 26% in patients with triglyceride levels ≥150 mg/dL before the administration. No difference between the elderly and the non-elderly subjects in the decline of total cholesterol was observed.
Furthermore, a long-term administration study (28-52 weeks) in patients with hypercholesterolemia indicated sustained and stable serum lipids improvement. Moreover, stable decrease in total cholesterol value and that of LDL-cholesterol value were observed on the long-term administration study (52-104 weeks) in patients with familial hypercholesterolemia.
Livazo 2mg has not been proven to prevent the associated complications of lipid abnormalities eg, coronary heart disease as mortality and morbidity studies with Livazo 2mg have not yet been completed.
Effect on Blood Steroid Hormones in the Elderly:
Oral administration of Livazo 2mg calcium 2 mg once a day for 8 weeks in 34 hyperlipidemic patients ≥70 years indicated no significant change on the blood steroid hormones.
Effect on Sugar Metabolism in Hyperlipidemic Patients with Concomitant Diabetes:
Oral administration of Livazo 2mg calcium 2 mg once a day for 8 weeks in 33 hyperlipidemic patients with concomitant non-insulin dependent diabetes affected a little on the blood sugar control.
How should I take Livazo 2mg?
Take Livazo 2mg only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.
In addition to Livazo 2mg, your doctor may change your diet to one that is low in fat, sugar, and cholesterol. Carefully follow your doctor's orders about any special diet.
You may take Livazo 2mg with or without food.
Do not drink large amounts of alcohol while taking Livazo 2mg. This could cause unwanted side effects on the liver.
Dosing
The dose of Livazo 2mg will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Livazo 2mg. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
- For oral dosage form (tablets):
- For high cholesterol:
- Adults—At first, 2 milligrams (mg) once a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 4 mg per day.
- Children—Use and dose must be determined by your doctor.
- For high cholesterol:
Missed Dose
If you miss a dose of Livazo 2mg, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Storage
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Livazo 2mg administration
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Livazo 2mg is usually taken once a day, with or without food. Take the medicine at the same time each day. Your doctor may occasionally change your dose to make sure you get the best results.
You may need to stop using Livazo 2mg for a short time if you have:
- uncontrolled seizures;
- an electrolyte imbalance (such as high or low potassium levels in your blood);
- severely low blood pressure;
- a severe infection or illness;
- dehydration; or
- surgery or a medical emergency.
To be sure this medicine is helping your condition and is not causing harmful effects, your blood will need to be tested often. Visit your doctor regularly.
Livazo 2mg is only part of a complete program of treatment that also includes diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely.
Store at room temperature away from moisture, heat, and light.
Livazo 2mg pharmacology
Mechanism Of Action
Livazo 2mg competitively inhibits HMG-CoA reductase, which is a rate-determining enzyme involved with biosynthesis of cholesterol, in a manner of competition with the substrate so that it inhibits cholesterol synthesis in the liver. As a result, the expression of LDL-receptors followed by the uptake of LDL from blood to liver is accelerated and then the plasma TC decreases. Further, the sustained inhibition of cholesterol synthesis in the liver decreases levels of very low density lipoproteins.
Pharmacodynamics
In a randomized, double-blind, placebo-controlled, 4-way parallel, active-comparator study with moxifloxacin in 174 healthy participants, Livazo 2mg was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 16 mg (4 times the recommended maximum daily dose).
Pharmacokinetics
Absorption
Livazo 2mg peak plasma concentrations are achieved about 1 hour after oral administration. Both Cmax and AUC0-inf increased in an approximately dose-proportional manner for single Livazo 2mg doses from 1 to 24 mg once daily. The absolute bioavailability of Livazo 2mg oral solution is 51%. Administration of Livazo 2mg with a high fat meal (50% fat content) decreases Livazo 2mg Cmax by 43% but does not significantly reduce Livazo 2mg AUC. The Cmax and AUC of Livazo 2mg did not differ following evening or morning drug administration. In healthy volunteers receiving 4 mg Livazo 2mg, the percent change from baseline for LDL-C following evening dosing was slightly greater than that following morning dosing. Livazo 2mg was absorbed in the small intestine but very little in the colon.
Distribution
Livazo 2mg is more than 99% protein bound in human plasma, mainly to albumin and alpha 1-acid glycoprotein, and the mean volume of distribution is approximately 148 L. Association of Livazo 2mg and/or its metabolites with the blood cells is minimal.
Metabolism
Livazo 2mg is marginally metabolized by CYP2C9 and to a lesser extent by CYP2C8. The major metabolite in human plasma is the lactone which is formed via an ester-type Livazo 2mg glucuronide conjugate by uridine 5'-diphosphate (UDP) glucuronosyltransferase (UGT1A3 and UGT2B7).
Excretion
A mean of 15% of radioactivity of orally administered, single 32 mg C-labeled Livazo 2mg dose was excreted in urine, whereas a mean of 79% of the dose was excreted in feces within 7 days. The mean plasma elimination half-life is approximately 12 hours.
Race
In pharmacokinetic studies Livazo 2mg Cmax and AUC were 21 and 5% lower, respectively in Black or African American healthy volunteers compared with those of Caucasian healthy volunteers. In pharmacokinetic comparison between Caucasian volunteers and Japanese volunteers, there were no significant differences in Cmax and AUC.
Gender
In a pharmacokinetic study which compared healthy male and female volunteers, Livazo 2mg Cmax and AUC were 60 and 54% higher, respectively in females. This had no effect on the efficacy or safety of Livazo 2mg in women in clinical studies.
Geriatric
In a pharmacokinetic study which compared healthy young and elderly ( ≥ 65 years) volunteers, Livazo 2mg Cmax and AUC were 10 and 30% higher, respectively, in the elderly. This had no effect on the efficacy or safety of Livazo 2mg in elderly subjects in clinical studies.
Renal Impairment
In patients with moderate renal impairment (glomerular filtration rate of 30 - 59 mL/min/1.73 m²) and end stage renal disease receiving hemodialysis, Livazo 2mg AUC0-inf is 102 and 86% higher than those of healthy volunteers, respectively, while Livazo 2mg Cmax is 60 and 40% higher than those of healthy volunteers, respectively. Patients received hemodialysis immediately before Livazo 2mg dosing and did not undergo hemodialysis during the pharmacokinetic study. Hemodialysis patients have 33 and 36% increases in the mean unbound fraction of Livazo 2mg as compared to healthy volunteers and patients with moderate renal impairment, respectively.
In another pharmacokinetic study, patients with severe renal impairment (glomerular filtration rate 15 - 29 mL/min/1.73 m²) not receiving hemodialysis were administered a single dose of Livazo 2mg 4 mg. The AUC0-inf and the Cmax were 36 and 18% higher, respectively, compared with those of healthy volunteers. For both patients with severe renal impairment and healthy volunteers, the mean percentage of protein-unbound Livazo 2mg was approximately 0.6%.
The effect of mild renal impairment on Livazo 2mg exposure has not been studied.
Hepatic Impairment
The disposition of Livazo 2mg was compared in healthy volunteers and patients with various degrees of hepatic impairment. The ratio of Livazo 2mg Cmax between patients with moderate hepatic impairment (Child-Pugh B disease) and healthy volunteers was 2.7. The ratio of Livazo 2mg AUCinf between patients with moderate hepatic impairment and healthy volunteers was 3.8. The ratio of Livazo 2mg Cmax between patients with mild hepatic impairment (Child-Pugh A disease) and healthy volunteers was 1.3. The ratio of Livazo 2mg AUCinf between patients with mild hepatic impairment and healthy volunteers was 1.6. Mean Livazo 2mg t½ for moderate hepatic impairment, mild hepatic impairment, and healthy were 15, 10, and 8 hours, respectively.
Drug-Drug Interactions
The principal route of Livazo 2mg metabolism is glucuronidation via liver UGTs with subsequent formation of Livazo 2mg lactone. There is only minimal metabolism by the cytochrome P450 system.
Warfarin
The steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the co-administration of Livazo 2mg 4 mg daily. However, patients receiving warfarin should have their PT time or INR monitored when Livazo 2mg is added to their therapy.
Table 2: Effect of Co-Administered Drugs on Livazo 2mg Systemic Exposure
NL=non-inferiority limit.
References
- DailyMed. "PITAVASTATIN CALCIUM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Pitavastatin: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Pitavastatin: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
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Information checked by Dr. Sachin Kumar, MD Pharmacology
