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| __NOTOC__
| | #REDIRECT [[Pitavastatin#Pharmacology]] |
| {{Pitavastatin}}
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| {{CMG}}; {{AE}} {{SS}}
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| ==Clinical Pharmacology==
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| ===Mechanism of Action===
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| 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.
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| ===Pharmacodynamics===
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| In a randomized, double-blind, placebo-controlled, 4-way parallel, active-comparator study with [[moxifloxacin]] in 174 healthy participants, LIVALO 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).
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| ===Pharmacokinetics===
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| '''Absorption''': Pitavastatin 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 LIVALO doses from 1 to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%. Administration of LIVALO with a high fat meal (50% fat content) decreases pitavastatin Cmax by 43% but does not significantly reduce pitavastatin AUC. The Cmax 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.
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| '''Distribution''': Pitavastatin 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 pitavastatin and/or its metabolites with the blood cells is minimal.
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| '''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).
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| '''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.
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| '''Race''': In pharmacokinetic studies pitavastatin 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.
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| '''Gender''': In a pharmacokinetic study which compared healthy male and female volunteers, pitavastatin Cmax and AUC were 60 and 54% higher, respectively in females. This had no effect on the efficacy or safety of LIVALO in women in clinical studies.
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| '''Geriatric''': In a pharmacokinetic study which compared healthy young and elderly (≥65 years) volunteers, pitavastatin Cmax and AUC were 10 and 30% higher, respectively, in the elderly. This had no effect on the efficacy or safety of LIVALO in elderly subjects in clinical studies.
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| '''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 AUC0-inf is 102 and 86% higher than those of healthy volunteers, respectively, while pitavastatin Cmax 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.
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| 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 LIVALO 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 pitavastatin was approximately 0.6%.
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| The effect of mild [[renal impairment]] on pitavastatin exposure has not been studied.
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| '''Hepatic Impairment''': The disposition of pitavastatin was compared in healthy volunteers and patients with various degrees of hepatic impairment. The ratio of pitavastatin Cmax between patients with moderate [[hepatic impairment]] (Child-Pugh B disease) and healthy volunteers was 2.7. The ratio of pitavastatin AUCinf between patients with moderate hepatic impairment and healthy volunteers was 3.8. The ratio of pitavastatin Cmax between patients with mild hepatic impairment (Child-Pugh A disease) and healthy volunteers was 1.3. The ratio of pitavastatin AUCinf between patients with mild hepatic impairment and healthy volunteers was 1.6. Mean pitavastatin t½ for moderate hepatic impairment, mild hepatic impairment, and healthy were 15, 10, and 8 hours, respectively.
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| '''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.
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| '''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 LIVALO 4 mg daily. However, patients receiving [[warfarin]] should have their PT time or INR monitored when pitavastatin is added to their therapy.
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| {|
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| |[[File:Pitavastatin02.jpg|thumb|800px]]
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| |}
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| {|
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| |[[File:Pitavastatin03.jpg|thumb|800px]]
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| |}
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| <ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = LIVALO (PITAVASTATIN CALCIUM) TABLET, FILM COATED [KOWA PHARMACEUTICALS AMERICA, INC. ] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=44dcbf97-99ec-427c-ba50-207e0069d6d2 | publisher = | date = | accessdate = 14 February 2014 }}</ref>
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| ==References==
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| {{Reflist|2}}
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| {{statins}}
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| [[Category:Statins]]
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| [[Category:Quinolines]]
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| [[Category:Diols]]
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| [[Category:Carboxylic acids]]
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| [[Category:Organofluorides]]
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| [[Category:Cyclopropanes]]
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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