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Pitavastatin 於降血脂的研究
Pitavastatin: Efficacy and Safety Profiles
of A Novel Synthetic HMG-CoA Reductase
Inhibitor
Kouji Kajinami,1 Noboru Takekoshi,1 and Yasushi Saito2
1Department of Cardiology, Kanazawa Medical University, Japan;
2The Second Department of Clinical Biology,
Graduate School of Medicine, Chiba University, Japan
ABSTRACT
The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors,
statins, has been shown to reduce major cardiovascular events in both primary and secondary
prevention, and statins became one of the most widely prescribed classes of drugs
throughout the world. Previously, statins have been well tolerated and have shown favorable
safety profiles. However, the voluntary withdrawal of cerivastatin from the market
because of a disproportionate number of reports of rhabdomyolysis-associated deaths
drew attention to the pharmacokinetic profile of statins, which may possibly have been related
to serious drug-drug interactions.
Pitavastatin (NK-104, previously called itavastatin or nisvastatin, Kowa Company
cholesterol-lowering
action. The short-term and long-term lipid-modifying effects of pitavastatin have already
been investigated in subjects with primary hypercholesterolemia, heterozygous familial
hypercholesterolemia, hypertriglyceridemia, and type-2 diabetes mellitus accompanied
by hyperlipidemia. Within the range of daily doses from 1 to 4 mg, the efficacy of pitavastatin
as a lipid-lowering drug seems to be similar, or potentially superior, to that of
atorvastatin.
According to the results of pharmacokinetic studies, pitavastatin showed favorable and
promising safety profile; it was only slightly metabolized by the cytochrome P450 (CYP)
system, its lactone form had no inhibitory effects on the CYP3A4-mediated metabolism of
concomitantly administered drugs; P-glycoprotein-mediated transport did not play a major
role in its disposition, and pitavastatin did not inhibit P-glycoprotein activity.
INTRODUCTION
Pitavastatin (NK-104, previously called itavastatin or nisvastatin) is a chemically synthesized
statin, which was developed by Kowa Company Ltd. Tokyo, Japan. It has been
shown that pitavastatin is a powerful statin and has favorable pharmacokinetic properties
which are likely to limit drug-drug interactions (29). In this article, we focus on the pharmacokinetic
profile, clinical efficacy and safety, as well as the antiatherosclerotic potential of pitavastatin.
Pitavastatin is an enantiomer (3R,5S) with a dihydroxypentenoic acid chain (Fig. 1)
synthesized by Nissan Chemical Industries, Ltd., Tokyo, Japan, and developed by Kowa
Co., Ltd., Tokyo, Japan. Its chemical name is: (+)-monocalcium bis(3R,5S,6E)-7-[2-cyclopropyl-
4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate (C50H46CaF2N2O8).
Its molecular weight is 880.98 (63,65). Pitavastatin is classified as a lipophilic drug. Its
log P is 1.49, which suggests that it is moderately lipophilic in comparison to other lipo-philic statins, such as simvastatin (1.88 in acid form and 4.40 in lactone form) and atorvastatin (1.53) (60). The lipophilicity is one of the important chemical properties of pitavastatin.
CONCLUSIONS
In accordance with the reviewed data pitavastatin reduces LDL cholesterol dose-dependently,
and its efficacy appears to be equivalent to that of atorvastatin. The favorable
pharmacokinetic properties of this new statin strongly suggest greater safety as the clinical
advantage of this agent. In conclusion, pitavastatin can provide a new and potentially
better therapeutic choice for lipid-modifying therapy than other currently available statins.
The efficacy and safety of pitavastatin at higher doses, as well as its long-term effects in
the prevention of coronary artery disease, should be studied to fully characterize the clinical
Pitavastatin: a New 3-Hydroxy-3-Methylglutaryl
Coenzyme A Reductase Inhibitor for the Treatment of
Hyperlipidemia
William L. Baker · Rupangi Datta
Received: October 1, 2010 / Published online: December 9, 2010 c Springer Healthcare 2010
ABSTRACT
Statins have proven beneficial for reducing both primary and secondary events in patients with coronary heart disease. Tight control of serum lipid parameters in these patients is recommended by the most recent clinical guidelines. Although numerous
lipidlowering treatments are available, only a small percentage of eligible patients receive therapy and fewer achieve their
lipid-lowering goals. Thus it is clear that new treatment strategies to manage patients with lipid abnormalities are warranted.
Pitavastatin (LivaloR; Kowa Pharmaceuticals America, Montgomery, AL, USA) has been recently approved for
the treatment of hypercholesterolemia and combined dyslipidemia. Pitavastatin 1-4 mg/day
has shown similar low-density lipoproteinreducing activity to other commercially available statins, including simvastatin and
atorvastatin. Adverse events occurred at similar rates to other statins in clinical trials with favorable effects seen in patients with dyslipidemia and metabolic syndrome. Pharmacokinetic drugdrug interactions are minimized due to the lack of significant metabolism of pitavastatin by the cytochrome P450 enzyme system, although some drugs affect its uptake into hepatocytes and should be avoided. In addition to its higher acquisition cost, pitavastatin has not been shown to improve clinical outcomes in high-risk patient
populations and thus may not be the agent of choice in many patients at this time in lieu of cheaper, clinically proven alternatives. Keywords: HMG-CoA reductase inhibitor; hypercholesterolemia; hyperlipidemia; pitavastatin; statin
ADVERSE EVENTS
The most common general tolerance adverse events associated with use of pitavastatin include
back pain, constipation, diarrhea, abdominal pain, and dizziness with incidences ranging from
2% to 4%, similarly to other currently available statins.16 Elevations of blood creatinine kinase (CK), the most commonly reported adverse event in clinical trials, occurred in 5.8% of patients receiving pitavastatin.66 No differences in the incidence of CK elevations were noted in clinical trials compared with atorvastatin.49,51
The manufacturer’s literature recommends discontinuation of pitavastatin therapy if CK levels markedly increase or are
associated with myopathy.16 Kobayashi and colleagues examined the mechanism involved with muscle cytotoxicity associated with statins and provided the following rank order for the class: cerivastatin > simvastatin > fluvastatin > atorvastatin > lovastatin >
pitavastatin >> rosuvastatin, pravastatin.67 Another concerning adverse event with the statin class is elevations in liver function tests
(LFTs). Clinical trials have shown that increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than three times the upper limit of normal have been seen in 0.5% of patients receiving the pitavastatin 4 mg/day dose. Abnormalities in AST and ALT have not been routinely seen with lower doses, although the manufacturer recommends that LFTs be monitored before, at 12 weeks, and periodically after the initiation of pitavastatin therapy.16 Evidence has suggested that statins may have adverse effects on markers of insulin sensitivity, including the homeostasis mode assessment for insulin resistance (HOMA-IR), although differences between agents in the class may exist.68 Clinical studies have shown that no significant differences exist between pitavastatin and atorvastatin regarding their
impact on fasting glucose, hemoglobin A1c, or HOMA-IR.51,69 DRUG INTERACTIONS
Various clinically relevant drug-drug interactions have been demonstrated with pitavastatin as a result of inhibition of the OATP
enzyme that is responsible for uptake of pitavastatin into human hepatocytes.70
Several drugs have been found to interact with OATP1B1-mediated pitavastatin uptake including cyclosporine, rifampin,
clarithromycin, and indinavir.70,71 As a result, the concomitant use of pitavastatin
with cyclosporine is contraindicated, with lower dosing recommendations required with erythromycin and rifampin
coadministration.16 Coadministration of statins with fibric acid derivatives, including gemfibrozil, has historically been avoided due to a proposed increased risk for myopathy as a result of a pharmacokinetic drug-drug interaction. Various studies have demonstrated that plasma levels of pitavastatin are not appreciably affected by either gemfibrozil or fenofibrate in vitro and in healthy volunteers.72-74 Similarly, concomitant ingestion of grapefruit juice with pitavastatin did not demonstrate clinically significant
alterations to its pharmacokinetics, although Pitavastatin
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