Pitator Mechanism of Action

Pharmacology: Mechanism of Action: Pitavastatin 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: The magnitude of LDL-C reduction by pitavastatin (2 mg and 4 mg) is comparable to atorvastatin (10 mg and 20 mg) and simvastatin (20 mg and 40 mg). It also does not prolong the QTc interval to a clinically significant degree.
Pharmacokinetics: Absorption: Pitavastatin peak plasma concentrations are achieved about 1 hour after oral administration. Both C_max and AUC_0-inf increased in an approximately dose-proportional manner for single Pitavastatin doses from 1 to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%. Administration of Pitavastatin with a high fat meal (50% fat content) decreases pitavastatin C_max by 43% but does not significantly reduce pitavastatin AUC. The C_max and AUC of pitavastatin did not differ following evening or morning drug administration. In healthy volunteers receiving 4 mg pitavastatin, the percent change from baseline for LDL-C following evening dosing was slightly greater than that following morning dosing. Pitavastatin was absorbed in the small intestine but very little in the colon.
Distribution: Pitavastatin is more than 99% protein bound in human plasma, mainly to albumin and α1-acid glycoprotein, and the mean volume of distribution is approximately 148 L. Association of pitavastatin and/or its metabolites with the blood cells is minimal.
Metabolism: Pitavastatin 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 pitavastatin glucuronide conjugate by uridine 5'-diphosphate (UDP) glucuronosyltransferase (UGT1A3 and UGT2B7).
Excretion: A mean of 15% of radioactivity of orally administered, single 32 mg ¹⁴C-labeled pitavastatin 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, pitavastatin C_max 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 C_max and AUC.
Gender: In a pharmacokinetic study which compared healthy male and female volunteers, pitavastatin C_max and AUC were 60 and 54% higher, respectively in females. This had no effect on the efficacy or safety of Pitavastatin in women in clinical studies.
Geriatric: In a pharmacokinetic study which compared healthy young and elderly (≥ 65 years) volunteers, pitavastatin C_max and AUC were 10 and 30% higher, respectively, in the elderly. This had no effect on the efficacy or safety of Pitavastatin 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, pitavastatin AUC_0-inf is 102 and 86% higher than those of healthy volunteers, respectively, while pitavastatin C_max is 60 and 40% higher than those of healthy volunteers, respectively. Patients received hemodialysis immediately before pitavastatin dosing and did not undergo hemodialysis during the pharmacokinetic study. Hemodialysis patients have 33 and 36% increases in the mean unbound fraction of pitavastatin 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 Pitavastatin 4 mg. The AUC_0-inf and the C_max 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 pitavastatin was approximately 0.6%. The effect of mild renal impairment on pitavastatin exposure has not been studied.
Hepatic Impairment: The disposition of pitavastatin was compared in healthy volunteers and patients with various degrees of hepatic impairment. The ratio of pitavastatin C_max between patients with moderate hepatic impairment (Child-Pugh B disease) and healthy volunteers was 2.7. The ratio of pitavastatin AUC_inf between patients with moderate hepatic impairment and healthy volunteers was 3.8. The ratio of pitavastatin C_max between patients with mild hepatic impairment (Child-Pugh A disease) and healthy volunteers was 1.3. The ratio of pitavastatin AUC_inf between patients with mild hepatic impairment and healthy volunteers was 1.6. Mean pitavastatin t_½ for moderate hepatic impairment, mild hepatic impairment, and healthy were 15, 10, and 8 hours, respectively.
Drug-Drug Interactions: The principal route of pitavastatin metabolism is glucuronidation via liver UGTs with subsequent formation of pitavastatin 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 Pitavastatin 4 mg daily. However, patients receiving warfarin should have their PT time or INR monitored when pitavastatin is added to their therapy.