Pitavastatin 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:
Pitavastatin 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:
Pitavastatin 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 pitavastatin calcium (dogs, guinea pigs).
Suppressing Effects on Lipid Accumulation and Intimal Thickening:
Pitavastatin 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:
Pitavastatin 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 pitavastatin 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 pitavastatin calcium (2 mg or 4 mg) was performed under fasted conditions. Unchanged pitavastatin and its lactone, the main metabolite, were mainly found in plasma. The pharmacokinetic parameters after the administration of pitavastatin 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 (see Table 1).
Click on icon to see table/diagram/image
Blood Concentration After Repeated Oral Administration:
After repeated oral administration of pitavastatin 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. (See Table 2.)
Click on icon to see table/diagram/image
Furthermore, after a 5-day repeated oral administration of pitavastatin 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 pitavastatin 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 pitavastatin calcium on day 6. The plasma concentration of the unchanged pitavastatin 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 pitavastatin calcium 4 mg was performed followed by 1-day washout and then 7-day repeated oral co-administration of pitavastatin calcium 4 mg and fenofibrate or gemfibrozil. The plasma concentrations on the unchanged pitavastatin (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 pitavastatin 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 pitavastatin 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.
After single oral administration of pitavastatin calcium 2 mg or 4 mg in 6 healthy adult male humans, the urinary excretion rate of the unchanged pitavastatin was <0.6%, and that of its lactone metabolite was <1.3%. The total excretion rate of the unchanged pitavastatin and its lactone was <2% of the dose.
After 7-day repeated oral dose of pitavastatin 4 mg once a day in 6 healthy adult human males, the urinary excretion of the unchanged pitavastatin and its lactone metabolite showed no increase during the period from the first administration until day 7 and decreased rapidly after completion of administration.
Pitavastatin 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 pitavastatin 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 pitavastatin, its lactone, dehydro-lactone, 8-hydroxide and these conjugates were minimally observed in urine.
Pitavastatin 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 pitavastatin 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 pitavastatin 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
The aggregated result of clinical studies (including a double-blind comparative study) by the administration of pitavastatin (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.
Livalo has not been proven to prevent the associated complications of lipid abnormalities eg, coronary heart disease as mortality and morbidity studies with Livalo have not yet been completed.
Effect on Blood Steroid Hormones in the Elderly:
Oral administration of pitavastatin 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 pitavastatin 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.