Pitavastatin

421.46

421.46

M5681Q5F9P

DTXSID4046448|DTXSID1048384|DTXSID50694059

C87751

C - Cardiovascular system

3004909090

90.65000

3.45

1.352±0.06 g/cm3(Predicted)

692.0±55.0 °C(Predicted)

372.3±31.5 °C

1.680

Very slightly soluble

Store at room temperature between 15 °C and 30 °C (59 deg to 86 °F). Protect from light.

2.32X10-17 mm Hg at 25 °C (est)

Henry's Law constant = 0.89X10-19 atm-cu m/mol at 25 °C (est)

pKa = 4.3 (carboxy) (est)

MW: 493.45. MP: 138-139 °C. Specific optical rotation: +8.84 deg at 32 °C/D (c = 0.92 in chloroform). Soluble in acetonitrile /Pitavastatin lactone/|Hydroxyl radical reaction rate constant = 1.00X10-11 cu cm/molecule-sec at 25 °C (cis); 1.08X10-11 cu cm/molecule-sec at 25 °C (trans) (est)|Ozone reaction rate constant = 6.82X10-17 cu cm/molecule-sec at 25 °C (cis); 1.36X10-16 cu cm/molecule-sec at 25 °C (trans) (est)

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including pitavastatin calcium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Pitavastatin calcium/

|Warning|H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]|P201, P202, P260, P263, P264, P270, P281, P308+P313, P405, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

IDENTIFICATION AND USE: Pitavastatin, a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (i.e., statin), is an antilipemic agent. It is used as an adjunct to lifestyle modifications for the management of dyslipidemias. HUMAN EXPOSURE AND TOXICITY: Pitavastatin is contraindicated for use in pregnant women or patients with active liver disease, including unexplained, persistent elevations in serum aminotransferase concentrations. Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including pitavastatin. These risks can occur at any dose level, but increase in a dose-dependent manner. Cases of fatal and nonfatal hepatic failure have also been reported rarely in patients receiving pitavastatin. ANIMAL STUDIES: In a 92-week carcinogenicity study in mice given pitavastatin, at the maximum tolerated dose of 75 mg/kg/day there was an absence of drug-related tumors. However, in a 92-week carcinogenicity study in rats given pitavastatin at 1, 5, 25 mg/kg/day by oral gavage, there was a significant increase in the incidence of thyroid follicular cell tumors at 25 mg/kg/day. Embryo-fetal developmental studies were conducted in pregnant rats treated with 3, 10, 30 mg/kg/day pitavastatin by oral gavage during organogenesis. No adverse effects were observed at 3 mg/kg/day. Embryo-fetal developmental studies were conducted in pregnant rabbits treated with 0.1, 0.3, 1 mg/kg/day pitavastatin by oral gavage during the period of fetal organogenesis. Maternal toxicity consisting of reduced body weight and abortion was observed at all doses tested. In perinatal/postnatal studies in pregnant rats given oral gavage doses of pitavastatin at 0.1, 0.3, 1, 3, 10, 30 mg/kg/day from organogenesis through weaning, maternal toxicity consisting of mortality at 0.3 mg/kg/day and impaired lactation at all doses contributed to the decreased survival of neonates in all dose groups. Pitavastatin had no adverse effects on male and female rat fertility at oral doses of 10 and 30 mg/kg/day, respectively. Pitavastatin was not mutagenic in the Ames test with Salmonella typhimurium and Escherichia coli with and without metabolic activation, the micronucleus test following a single administration in mice and multiple administrations in rats, the unscheduled DNA synthesis test in rats, and a Comet assay in mice. In the chromosomal aberration test, clastogenicity was observed at the highest doses tested which also elicited high levels of cytotoxicity.

Because pitavastatin is a relatively new agent, less information is available on its potential hepatotoxicity. In large clinical trials, pitavastatin therapy was associated with mild, asymptomatic and usually transient serum aminotransferase elevations in approximately 1% of patients, but levels above 3 times the upper limit of normal (ULN) were infrequent and no cases of clinically apparent hepatitis were reported from the preregistration clinical trials. Since marketing of pitavastatin, however, the sponsor has received reports of jaundice, hepatitis and hepatic failure including fatal cases. There has been only a single published report of liver injury due to pitavastatin, so that the clinical signature of hepatic injury associated with its use has not been defined. On the other hand, the other statins have all been implicated in cases of clinically apparent acute liver injury that typically arise after 1 to 6 months of therapy with either a cholestatic or hepatocellular pattern of serum enzyme elevations. Rash, fever and eosinophilia are uncommon, but some cases have been marked by autoimmune features including autoantibodies, chronic hepatitis on liver biopsy and a clinical response to corticosteroid therapy. This pattern has yet to be shown to apply to pitavastatin.

Pitavastatin is a substrate of organic anionic transport polypeptide (OATP) 1B1 (OATP2). Drugs that inhibit OATP1B1 (e.g., cyclosporine, erythromycin, rifampin) can increase bioavailability of pitavastatin.|Concomitant use of pitavastatin (2 mg once daily) and ezetimibe (10 mg for 7 days) decreased pitavastatin peak plasma concentration and AUC by 2 and 0.2%, respectively, and increased ezetimibe peak plasma concentration and AUC by 9 and 2%, respectively.|Erythromycin substantially increases pitavastatin exposure.1 Following concomitant use of pitavastatin (4 mg as a single dose on day 4) and erythromycin (500 mg 4 times daily for 6 days), pitavastatin peak plasma concentration and AUC were increased by 3.6- and 2.8-fold, respectively; such effects were considered clinically important. The interaction between pitavastatin and erythromycin probably resulted partly from erythromycin-induced inhibition of organic anionic transport polypeptide (OATP)1B1-mediated hepatic uptake of pitavastatin. If used concomitantly with erythromycin, dosage of pitavastatin should not exceed 1 mg once daily.|Concomitant use of pitavastatin (4 mg once daily on days 1-5 and 11-15) and extended-release diltiazem hydrochloride (240 mg on days 6-15) increased pitavastatin peak plasma concentration and AUC by 15 and 10%, respectively, and decreased diltiazem peak plasma concentration and AUC by 7 and 2%, respectively.|For more Interactions (Complete) data for Pitavastatin (20 total), please visit the HSDB record page.

Livalo is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides (TG) increase during normal pregnancy, and cholesterol products are essential for fetal development.|Pitavastatin should be used with caution in patients who consume substantial amounts of alcohol. The drug is contraindicated in patients with active liver disease, including unexplained, persistent elevations in serum aminotransferase concentrations.

Pitavstatin is more than 99% protein bound in human plasma, mainly to albumin and alpha 1-acid glycoprotein.

Pitavastatin is indicated for the treatment of adult patients with primary hyperlipidemia or mixed dyslipidemia to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C). It is also indicated for the treatment of pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH) to reduce elevated TC, LDL-C, and Apo B. Prescribing of statin medications is considered standard practice following any cardiovascular events and for people with a moderate to high risk of development of CVD. Statin-indicated conditions include diabetes mellitus, clinical atherosclerosis (including myocardial infarction, acute coronary syndromes, stable angina, documented coronary artery disease, stroke, trans ischemic attack (TIA), documented carotid disease, peripheral artery disease, and claudication), abdominal aortic aneurysm, chronic kidney disease, and severely elevated LDL-C levels.

Pitavastatin is a relatively newly developed cholesterol lowering agent (statin) that is associated with mild, asymptomatic and self-limited serum aminotransferase elevations during therapy, but has had limited use and has yet to be linked with clinically apparent acute liver injury.

Antilipemic Agents

Hydroxymethylglutaryl-CoA Reductase Inhibitors|Livalo is indicated as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia. /Included in US product label/|The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline recommends statins as first-line therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in adults. Pitavastatin may be used for primary or secondary prevention in adults when moderate-intensity statin therapy is indicated. /NOT included in US product label/|/EXPL THER/ Pitavastatin classically functions as a blood cholesterol-lowering drug. Previously, it was discovered with antiglioma stem cell properties through drug screening. However, whether it can be used for liver cancer cell therapy has never been reported. In this study, the cell viability and colony formation assay were utilized to analyze the cytotoxicity of pitavastatin on liver cancer cells. The cell cycle alteration was checked after pitavastatin treatment. Apoptosis-related protein expression and the effect of caspase inhibitor were also checked. The in vivo inhibitory effect of pitavastatin on the growth of liver tumor was also tested. It was found that pitavastatin inhibited growth and colony formation of liver cancer Huh-7 cells and SMMC7721 cells. It induced arrest of liver cancer cells at the G1 phase. Increased proportion of sub-G1 cells was observed after pitavastatin treatment. Pitavastatin promoted caspase-9 cleavage and caspase-3 cleavage in liver cancer cells. Caspase inhibitor Z-VAD-FMK reversed the cleavage of cytotoxic effect of pitavastatin. Moreover, pitavastatin decreased the tumor growth and improved the survival of tumor-bearing mice. This study suggested the antiliver cancer effect of the old drug pitavastatin. It may be developed as a drug for liver cancer therapy.

Increases in serum aminotransferase (i.e., AST [SGOT], ALT [SGPT]) concentrations have been reported in patients receiving statins, including pitavastatin. These increases usually were transient and resolved or improved with continued therapy or after temporary interruption of therapy. In phase 2, placebo-controlled studies, increases in serum ALT concentrations exceeding 3 times the upper limit of normal occurred in 0.5% of patients receiving pitavastatin 4 mg daily. Cases of fatal and nonfatal hepatic failure have been reported rarely in patients receiving statins, including pitavastatin, during postmarketing surveillance.|Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has been reported rarely in patients receiving statins. Immune-mediated necrotizing myopathy is characterized by proximal muscle weakness and elevated creatine kinase (CK, creatine phosphokinase, CPK) concentrations that persist despite discontinuance of statin therapy, necrotizing myopathy without substantial inflammation, and improvement following therapy with immunosuppressive agents. Pitavastatin should be used with caution in patients with predisposing factors for myopathy (e.g., advanced age [older than 65 years of age], renal impairment, inadequately-treated hypothyroidism) and in patients receiving concomitant therapy with certain antilipemic agents (i.e., fibric acid derivatives, antilipemic dosages of niacin).|Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Livalo. These risks can occur at any dose level, but increase in a dose-dependent manner.|Pitavastatin is distributed into milk in rats. It is not known whether pitavastatin is distributed into human milk; however, a small amount of another statin is distributed into human milk. Because of the potential for serious adverse reactions from pitavastatin in nursing infants, the drug is contraindicated in nursing women. Women who require pitavastatin therapy should be advised not to breast-feed their infants or advised to discontinue pitavastatin.|For more Drug Warnings (Complete) data for Pitavastatin (26 total), please visit the HSDB record page.

Pitavastatin is an oral antilipemic agent which inhibits HMG-CoA reductase. It is used to lower total cholesterol, low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apoB), non-high density lipoprotein-cholesterol (non-HDL-C), and trigleride (TG) plasma concentrations while increasing HDL-C concentrations. High LDL-C, low HDL-C and high TG concentrations in the plasma are associated with increased risk of atherosclerosis and cardiovascular disease. The total cholesterol to HDL-C ratio is a strong predictor of coronary artery disease and high ratios are associated with higher risk of disease. Increased levels of HDL-C are associated with lower cardiovascular risk. By decreasing LDL-C and TG and increasing HDL-C, rosuvastatin reduces the risk of cardiovascular morbidity and mortality. Elevated cholesterol levels, and in particular, elevated low-density lipoprotein (LDL) levels, are an important risk factor for the development of CVD. Use of statins to target and reduce LDL levels has been shown in a number of landmark studies to significantly reduce the risk of development of CVD and all-cause mortality. Statins are considered a cost-effective treatment option for CVD due to their evidence of reducing all-cause mortality including fatal and non-fatal CVD as well as the need for surgical revascularization or angioplasty following a heart attack. Evidence has shown that even for low-risk individuals (with <10% risk of a major vascular event occurring within 5 years) statins cause a 20%-22% relative reduction in major cardiovascular events (heart attack, stroke, coronary revascularization, and coronary death) for every 1 mmol/L reduction in LDL without any significant side effects or risks. **Skeletal Muscle Effects** Pitavastatin may cause myopathy (muscle pain, tenderness, or weakness with creatine kinase (CK) above ten times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria). Rare fatalities have occurred as a result of rhabdomyolysis with statin use, including pitavastatin. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. As dosages of pitavastatin greater than 4mg per day were associated with an increased risk of severe myopathy, the product monograph recommends a maximum daily dose of 4mg once daily. The risk of myopathy during treatment with pitavstatin may be increased with concurrent administration of interacting drugs such as [fenofibrate], [niacin], [gemfibrozil], an d [cyclosporine]. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with [colchicine], and caution should therefore be exercised when prescribing these two medications together. Real-world data from observational studies has suggested that 10-15% of people taking statins may experience muscle aches at some point during treatment. **Hepatic Dysfunction** Increases in serum transaminases have been reported with pitavastatin. In most cases, the elevations were transient and either resolved or improved on continued therapy or after a brief interruption in therapy. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pitavastatin. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. **Increases in HbA1c and Fasting Serum Glucose Levels** Increases in HbA1c and fasting serum glucose levels have been reported with statins, including pitavastatin. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices. An in vitro study found that [atorvastatin], [pravastatin], [rosuvastatin], and [pitavastatin] exhibited a dose-dependent cytotoxic effect on human pancreas islet β cells, with reductions in cell viability of 32, 41, 34 and 29%, respectively, versus control. Moreover, insulin secretion rates were decreased by 34, 30, 27 and 19%, respectively, relative to control.

Compounds that inhibit HYDROXYMETHYLGLUTARYL COA REDUCTASES. They have been shown to directly lower CHOLESTEROL synthesis. (See all compounds classified as Hydroxymethylglutaryl-CoA Reductase Inhibitors.)

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 pitavastatin doses from 1 mg to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%. 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. Compared to other statins, pitavastatin has a relatively high bioavailability, which has been suggested to occur due to enterohepatic reabsorption in the intestine following intestinal absorption. Genetic differences in the OATP1B1 (organic-anion-transporting polypeptide 1B1) hepatic transporter encoded by the SCLCO1B1 gene (Solute Carrier Organic Anion Transporter family member 1B1) have been shown to impact pitavastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c.521T>C single nucleotide polymorphism (SNP) in the gene encoding OATP1B1 (SLCO1B1) demonstrated that pitavastatin AUC was increased 3.08-fold for individuals homozygous for 521CC compared to homozygous 521TT individuals. Other statin drugs impacted by this polymorphism include [simvastatin], [pitavastatin], [atorvastatin], and [rosuvastatin]. Individuals with the 521CC genotype may be at increased risk of dose-related adverse effects including myopathy and rhabdomyolysis due to increased exposure to the drug.|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.|148 L|Following a single dose, the apparent mean oral clearance of pitavastatin is 43.4 L/h.|/MILK/ It is not known whether pitavastatin is excreted in human milk, however, it has been shown that a small amount of another drug in this class passes into human milk. Rat studies have shown that pitavastatin is excreted into breast milk.|This study was addressed to understand the underlying mechanism of the substrate-dependent effect of genetic variation in SLCO1B1, which encodes OATP1B1 (organic anion transporting polypeptide) transporter, on the disposition of two OATP1B1 substrates, pravastatin and pitavastatin, in relation to their transport activities. The uptake of pravastatin, pitavastatin, and fluvastatin was measured in oocytes overexpressing SLCO1B1*1a and SLCO1B1*15 to compare the alterations of in-vitro transporting activity. After 40-mg pravastatin or 4-mg pitavastatin was administered to 11 healthy volunteers with homozygous genotypes of SLCO1B1*1a/*1a and SLCO1B1*15/*15, the pharmacokinetic parameters of pravastatin and pitavastatin were compared among participants with SLCO1B1*1a/*1a and SLCO1B1*15/*15 genotypes. The uptake of pravastatin and pitavastatin in SLCO1B1*15 overexpressing oocytes was decreased compared with that in SLCO1B1*15, but no change occurred with fluvastatin. The fold change of in-vitro intrinsic clearance (Clint) for pitavastatin in SLCO1B1*15 compared with SLCO1B1*1a was larger than that of pravastatin (P<0.0001). The clearance (Cl/F) of pitavastatin was decreased to a greater degree in participant with SLCO1B1*15/*15 compared with that of pravastatin in vivo (P<0.01), consistent with in-vitro study. As a result, Cmax and area under the plasma concentration-time curve of these nonmetabolized substrates were increased by SLCO1B1*15 variant. The greater decrease in the transport activity for pitavastatin in SLCO1B1*15 variant compared with SLCO1B1*1a was, however, associated with the greater effect on the pharmacokinetics of pitavastatin compared with pravastatin in relation to the SLCO1B1 genetic polymorphism. This study suggests that substrate dependency in the consequences of the SLCO1B1*15 variant could modulate the effect of SLCO1B1 polymorphism on the disposition of pitavastatin and pravastatin.|A pharmacokinetics study was conducted in 12 Chinese volunteers following a single dose of 1 mg, 2 mg and 4 mg of pitavastatin calcium in an open-label, randomized, three-period crossover design. Plasma concentrations of pitavastatin acid and pitavastatin lactone were determined by a HPLC method. Single-nucleotide polymorphisms (SNPs) in ABCB1, ABCG2, SLCO1B1, CYP2C9 and CYP3A5 were determined by TaqMan (MGB) genotyping assay. An analysis was performed on the relationship between the aforementioned SNPs and dose-normalized (based on 1 mg) area under the plasma concentration-time curve extrapolated to infinity [AUC(0-infinity)] and peak plasma concentration (Cmax) values of the acid and lactone forms of pitavastatin. Pitavastatin exhibited linear pharmacokinetics and great inter-subject variability. Compared to CYP2C9*1/*1 carriers, CYP2C9*1/*3 carriers had higher AUC(0-infinity) and Cmax of pitavastatin acid and AUC(0-infinity) of pitavastatin lactone (P<0.05). With respect to ABCB1 G2677T/A, non-G carriers had higher Cmax and AUC(0-infinity) of pitavastatin acid, and Cmax of pitavastatin lactone compared to GT, GA or GG genotype carriers (P<0.05). Gene-dose effects of SLCO1B1 c.521T> C and g.11187G > A on pharmacokinetics of the acid and lactone forms were observed. Compared to non-SLCO1B1*17 carriers, SLCO1B1*17 carriers had higher Cmax and AUC(0-infinity) of the acid and lactone forms (P<0.05). Significant sex difference was observed for pharmacokinetics of the lactone. Female SLCO1B1 521TT subjects had higher Cmax and AUC(0-infinity) of pitavastatin lactone compared to male 521TT subjects, however, such gender difference disappeared in 521 TC and 521CC subjects. Pitavastatin pharmacokinetics was not significantly affected by ABCB1 C1236T, ABCB1C3435T, CYP3A5*3, ABCG2 c.34G > A, c.421C > A, SLCO1B1 c.388A>G, c.571T>C and c.597C>T. We conclude that CYP2C9*3, ABCB1 G2677T/A, SLCO1B1 c.521T>C, SLCO1B1 g.11187G > A, SLCO1B1*17 and gender contribute to inter-subject variability in pitavastatin pharmacokinetics. Personalized medicine should be necessary for hypercholesterolemic patients receiving pitavastatin.|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.|For more Absorption, Distribution and Excretion (Complete) data for Pitavastatin (12 total), please visit the HSDB record page.

The principal route of pitavastatin metabolism is glucuronidation via liver uridine 5'-diphosphate glucuronosyltransferase (UGT) with subsequent formation of pitavastatin lactone. There is only minimal metabolism by the cytochrome P450 system. 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 UGTs (UGT1A3 and UGT2B7).|Pitavastatin has been studied for its effects on hepatic microsomal drug metabolism in rats, and the activities of several drug-metabolizing enzymes have been measured. No induction of the drug metabolizing enzymes (aniline hydroxylase, aminopyrine N-demethylase, 7-ethoxycoumarin O-deethylase and UDP-glucuronic acid transferase) was found in the pitavastatin group compared to the control after the multiple administrations of pitavastatin at the dosage of 1-10 mg/kg per day for 7 days. Based on several different in vitro approaches, it is concluded that CYP2C9 is the enzyme responsible for the metabolism of pitavastatin and no metabolite is present in renal and intestinal microsomes. The CYP2C9 polymorphism was not involved in the pitavastatin metabolism. No inhibitory effect in CYP-mediated metabolism was detected on the tolbutamide 4-hydroxylation (CYP2C9) and testosterone 6 beta-hydroxylation (CYP3A4) in the presence of pitavastatin. The results suggested that pitavastatin did not affect the drug-metabolizing systems.|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).|To elucidate any potential species differences, the in vitro metabolism of pitavastatin and its lactone was studied with hepatic and renal microsomes from rats, dogs, rabbits, monkeys and humans. With the addition of UDP-glucuronic acid to hepatic microsomes, pitavastatin lactone was identified as the main metabolite in several animals, including humans. Metabolic clearances of pitavastatin and its lactone in monkey hepatic microsome were much greater than in humans. M4, a metabolite of pitavastatin with a 3-dehydroxy structure, was converted to its lactone form in monkey hepatic microsomes in the presence of UDP-glucuronic acid as well as to pitavastatin. These results implied that lactonization is a common pathway for drugs such as 5-hydroxy pentanoic acid derivatives. The acid forms were metabolized to their lactone forms because of their structural characteristics. UDP-glucuronosyltransferase is the key enzyme responsible for the lactonization of pitavastatin, and overall metabolism is different compared with humans owing to the extensive oxidative metabolism of pitavastatin and its lactone in monkey.

The mean plasma elimination half-life is approximately 12 hours.|A mean of 15% of radioactivity of orally administered, single 32 mg (14)C-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.

Pitavastatin is a statin medication and a competitive inhibitor of the enzyme HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Pitavastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increase hepatic uptake of LDL, thereby reducing circulating LDL-C levels. In vitro and in vivo animal studies also demonstrate that statins exert vasculoprotective effects independent of their lipid-lowering properties, also known as the pleiotropic effects of statins. This includes improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response. Statins have also been found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an important role in leukocyte trafficking and in T cell activation.|Hepatic ATP-binding cassette transporter A1 (ABCA1) plays a key role in high-density lipoprotein (HDL) production by apolipoprotein A-I (ApoA-I) lipidation. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, increase ABCA1 mRNA levels in hepatoma cell lines ... . We investigated how statins increase ABCA1 in rat hepatoma McARH7777 cells. Pitavastatin, atorvastatin, and simvastatin increased total ABCA1 mRNA levels, whereas pravastatin had no effect. Pitavastatin also increased ABCA1 protein. Hepatic ABCA1 expression in rats is regulated by both liver X receptor (LXR) and sterol regulatory element-binding protein (SREBP2) pathways. Pitavastatin repressed peripheral type ABCA1 mRNA levels and its LXR-driven promoter, but activated the liver-type SREBP-driven promoter, and eventually increased total ABCA1 mRNA expression. Furthermore, pitavastatin increased peroxisome proliferator-activated receptor a (PPARa) and its downstream gene expression. Knockdown of PPARa attenuated the increase in ABCA1 protein, indicating that pitavastatin increased ABCA1 protein via PPARa activation, although it repressed LXR activation. Furthermore, the degradation of ABCA1 protein was retarded in pitavastatin-treated cells. These data suggest that pitavastatin increases ABCA1 protein expression by dual mechanisms: SREBP2-mediated mRNA transcription and PPARa-mediated ABCA1 protein stabilization, but not by the PPAR-LXR-ABCA1 pathway.|Pitavastatin competitively inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (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 low-density lipoprotein (LDL)-receptors followed by the uptake of LDL from blood to liver is accelerated and then the plasma total cholesterol (TC) decreases. Further, the sustained inhibition of cholesterol synthesis in the liver decreases levels of very low density lipoproteins.|Statin use in individuals with chronic obstructive pulmonary disease (COPD) with coexisting cardiovascular disease is associated with a reduced risk of exacerbations. ... To explore the mechanisms involved, we investigated the effect of statin on endothelial cell function, especially endothelial cell tight junctions. We primarily assessed whether pitavastatin could help mitigate the development of emphysema induced by continuous cigarette smoking (CS) exposure. We also investigated the activation of liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling, which plays a role in maintaining endothelial functions, important tight junction proteins, zonula occludens (ZO)-1 and claudin-5 expression, and lung microvascular endothelial cell permeability. RESULTS: We found that pitavastatin prevented the CS-induced decrease in angiomotin-like protein 1 (AmotL1)-positive vessels via the activation of LKB1/AMPK signaling and IFN-gamma-induced hyperpermeability of cultured human lung microvascular endothelial cells by maintaining the levels of AmotL1, ZO-1, and claudin-5 expression at the tight junctions. Our results indicate that the maintenance of lung microvascular endothelial cells by pitavastatin prevents tight junction protein dysfunctions induced by CS. ...

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|There is no known specific treatment in the event of overdose of pitavastatin. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis is unlikely to be of benefit due to high protein binding ratio of pitavastatin.

/SIGNS AND SYMPTOMS/ Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Livalo. These risks can occur at any dose level, but increase in a dose-dependent manner.|/SIGNS AND SYMPTOMS/ Cases of fatal and nonfatal hepatic failure have been reported rarely in patients receiving statins, including pitavastatin, during postmarketing surveillance.|/EPIDEMIOLOGY STUDIES/ ... We conducted a meta-analysis and employed indirect comparisons to identify differing risk effects across statins. We included any randomized clinical trial (RCT) of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin used for cardiovascular disease event prevention. The main outcome was adverse events [all-cause mortality, cancers, rhabdomylosis, diabetes, aspartate and alanine aminotransferase (AST/ALT), and creatinine kinase (CK) increases beyond the upper limit of normal]. In order to evaluate the relative effects of each drug on adverse events, we calculated adjusted indirect comparisons of the adverse-event outcomes. Seventy-two trials involving 159,458 patients met our inclusion criteria. Overall, statin treatments significantly increased the rate of diabetes when compared to controls (OR: 1.09; 95% CI: 1.02-1.16) and elevated AST (OR: 1.31; 95% CI: 1.04-1.66) and ALT (OR: 1.28; 95% CI: 1.11-1.48) levels when compared to controls. Using indirect comparisons, we also found that atorvastatin significantly elevated AST levels compared to pravastatin (OR: 2.21; 95% CI: 1.13-4.29) and simvastatin significantly increased CK levels when compared to rosuvastatin (OR: 4.39; 95% CI: 1.01-19.07). Higher dose studies had increased risk of AST elevations. Although statins are generally well tolerated, there are risks associated with almost all drugs. With few exceptions, statins appear to exert a similar risk across individual drugs.|/ALTERNATIVE and IN VITRO TESTS/ /The purpose of this study was/ to determine the effect of different statins on the induction of diabetes mellitus. Four statins (atorvastatin, pravastatin, rosuvastatin, and pitavastatin) were used. Cytotoxicity, insulin secretion, glucose-stimulated insulin secretion, and G0/G1 phase cell cycle arrest were investigated in human pancreas islet beta cells, and glucose uptake and signaling were studied in human skeletal muscle cells (HSkMCs). Human pancreas islet beta cells treated with 100 nM atorvastatin, pravastatin, rosuvastatin, and pitavastatin had reduced cell viability (32.12%, 41.09%, 33.96%, and 29.19%, respectively) compared to controls. Such cytotoxic effect was significantly attenuated by decreasing the dose to 10 and 1 nM, ranged from 1.46% to 17.28%. Cells treated with 100 nM atorvastatin, pravastatin, rosuvastatin, and pitavastatin had a reduction in the rate of insulin secretion rate by 34.07%, 30.06%, 26.78%, and 19.22%, respectively. The inhibitory effect was slightly attenuated by decreasing the dose to 10 and 1 nM, ranging from 10.84% to 29.60%. Insulin secretion stimulated by a high concentration of glucose (28 mmol/L) was significantly higher than a physiologic concentration of glucose (5.6 mmol/L) in all treatment groups. The glucose uptake rates at a concentration of 100 nM were as follows: atorvastatin (58.76%) < pravastatin (60.21%) < rosuvastatin (72.54%) < pitavastatin (89.96%). We also found that atorvastatin and pravastatin decreased glucose transporter (GLUT)-2 expression and induced p-p38 MAPK levels in human pancreas islet beta cells. Atorvastatin, pravastatin, and rosuvastatin inhibited GLUT-4, p-AKT, p-GSK-3beta, and p-p38 MAPK levels in HSkMCs. Statins similar but different degree of effects on pancreas islet beta cells damage and induce insulin resistance in HSkMC.|For more Human Toxicity Excerpts (Complete) data for Pitavastatin (9 total), please visit the HSDB record page.

(E,3R,5S)-7-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-3,5-dihydroxyhept-6-enoic acid

Table: Pitavastatin Calcium Preparations [Table#8408]

Degradation pathway for pitavastatin calcium is established as per ICH recommendations by validated and stability indicating reverse phase liquid chromatographic method. Pitavastatin is subjected to stress conditions of acid, base, oxidation, thermal and photolysis. Significant degradation is observed in acid and base stress conditions. Four impurities are studied among which impurity-4 is found prominent degradant. The stress samples are assayed against a qualified reference standard and the mass balance is found close to 99.5%. Efficient chromatographic separation is achieved on a BEH C18 stationary phase with simple mobile phase combination delivered in gradient mode and quantification is carried at 245 nm at a flow rate of 0.3 mL/min. In the developed UPLC method the resolution between pitavastatin calcium and four potential impurities is found to be greater than 4.0. Regression analysis shows an r value (correlation coefficient) of greater than 0.998 for pitavastatin calcium and four potential impurities. This method is capable to detect the impurities of pitavastatin calcium at a level of 0.006% with respect to test concentration of 0.10 mg/mL for a 2-uL injection volume. The developed UPLC method is validated with respect to specificity, linearity and range, accuracy, precision and robustness for impurities determination and assay determination.

Determination in plasma by HPLC. ... in plasma and urine by LC-MS/MS.

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