Pitavastatin: efficacy and safety profiles of a novel synthetic HMG-CoA reductase inhibitor.

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 Ltd., Tokyo) is a novel, fully synthetic statin, which has a potent 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. It could be concluded that pitavastatin could provide a new and potentially better therapeutic choice for lipid-modifying therapy than do the currently available statins. The efficacy and safety of higher dose treatment, as well as its long-term effects in the prevention of coronary artery disease, should be further investigated.

[1]  S. Singhvi,et al.  Biotransformation of pravastatin sodium in humans. , 1991, Drug metabolism and disposition: the biological fate of chemicals.

[2]  T. Leemann,et al.  In vivo inhibition profile of cytochrome P450TB (CYP2C9) by (±)‐fluvastatin , 1995, Clinical pharmacology and therapeutics.

[3]  P. Macfarlane,et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia , 1995 .

[4]  T. Leemann,et al.  In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors , 1996, European Journal of Clinical Pharmacology.

[5]  B. Davis,et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. , 1996, The New England journal of medicine.

[6]  M. Kitahara,et al.  Pharmacological profile of a novel synthetic inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. , 1997, Arzneimittel-Forschung.

[7]  H. Lennernäs,et al.  Pharmacodynamics and Pharmacokinetics of the HMG-CoA Reductase Inhibitors , 1997, Clinical pharmacokinetics.

[8]  R. Collins,et al.  Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. , 1998, The New England journal of medicine.

[9]  P. Neuvonen,et al.  Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid , 1998, Clinical pharmacology and therapeutics.

[10]  U. Christians,et al.  Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patients: are the statins mechanistically similar? , 1998, Pharmacology & therapeutics.

[11]  H. Fujino,et al.  Studies on the Metabolic Fate of NK-104, a New Inhibitor of HMG-CoA Reductase (1) : Absorption, Distribution, Metabolism and Excretion in Rats , 1998 .

[12]  S. Tanaka,et al.  NK-104, a newly developed HMG-CoA reductase inhibitor, suppresses neointimal thickening by inhibiting smooth muscle cell growth and fibronectin production in balloon-injured rabbit carotid artery. , 1998, Japanese journal of pharmacology.

[13]  A. Gotto,et al.  Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. , 1998, JAMA.

[14]  P. Neuvonen,et al.  Effect of itraconazole on the pharmacokinetics of atorvastatin , 1998, Clinical pharmacology and therapeutics.

[15]  H. Fujino,et al.  Studies on the Metabolic Fate of NK-104, a New Inhibitor of HMG-CoA Reductase (4) : Interspecies Variation in Laboratory Animals and Humans , 1999 .

[16]  V. Fischer,et al.  The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect on human cytochrome P-450 and implications for metabolic drug interactions. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[17]  M. Kitahara,et al.  Hypolipidemic effect of NK-104, a potent HMG-CoA reductase inhibitor, in guinea pigs. , 1999, Atherosclerosis.

[18]  J. Cha,et al.  NK-104, A Potent New 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, Enhances Posttranslational Catabolism of Apolipoprotein B-100 and Inhibits Secretion of Apolipoprotein B-100 and Triacylglycerols from HepG2 Cells , 1999 .

[19]  S. Harris,et al.  Stimulation of bone formation in vitro and in rodents by statins. , 1999, Science.

[20]  H. Y. Choo,et al.  Synthesis of piperazine derivatives and evaluation of their antihistamine and antibradykinin effects. , 1999, Bioorganic & medicinal chemistry letters.

[21]  K. Yamamoto,et al.  Effect of NK-104, a new synthetic HMG-CoA reductase inhibitor, on triglyceride secretion and fatty acid oxidation in rat liver. , 1999, Life sciences.

[22]  M. Hirano,et al.  Studies on the Metabolic Fate of NK-104, a New Inhibitor of HMG-CoA Reductase (5) : In Vitro Metabolism and Plasma Protein Binding in Animals and Human , 1999 .

[23]  Y. Yanagawa,et al.  First systematic chiral syntheses of two pairs of enantiomers with 3,5-dihydroxyheptenoic acid chain, associated with a potent synthetic statin NK-104. , 1999, Bioorganic & medicinal chemistry letters.

[24]  L. Kindred,et al.  Rhabdomyolysis and renal failure associated with cerivastatin-gemfibrozil combination therapy. , 1999, The American journal of cardiology.

[25]  S. Olson,et al.  Erythromycin Coadministration Increases Plasma Atorvastatin Concentrations , 1999, Journal of clinical pharmacology.

[26]  F. Bernini,et al.  New insights into the pharmacodynamic and pharmacokinetic properties of statins. , 1999, Pharmacology & therapeutics.

[27]  A. Catapano,et al.  NK-104, a potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, decreases apolipoprotein B-100 secretion from Hep G2 cells. , 1999, Atherosclerosis.

[28]  J. Sasaki,et al.  Efficacy and safety of a new HMG-CoA reductase inhibitor, NK-104, in patients with hypertriglyceridemia — Randomized double-blind, cross-over placebo controlled study , 2000 .

[29]  B. Ma,et al.  Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[30]  Yasushi Saito,et al.  Clinical evaluation of NK-104 (itavastatin) in long-term treatment of patients with hyperlipidemia , 2000 .

[31]  C. Higgins,et al.  New Nomenclature of Human ABC Transporter Genes , 2000 .

[32]  P. Neuvonen,et al.  Plasma concentrations of active simvastatin acid are increased by gemfibrozil , 2000, Clinical pharmacology and therapeutics.

[33]  T. Kodama,et al.  Relative induction of mRNA for HMG CoA reductase and LDL receptor by five different HMG-CoA reductase inhibitors in cultured human cells. , 2000, Journal of atherosclerosis and thrombosis.

[34]  H. Mabuchi,et al.  NK-104: a novel synthetic HMG-CoA reductase inhibitor , 2000, Expert opinion on investigational drugs.

[35]  W. Mück.  Clinical Pharmacokinetics of Cerivastatin , 2000, Clinical pharmacokinetics.

[36]  P. Kollman,et al.  Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[37]  B. H. Stewart,et al.  Atorvastatin Coadministration May Increase Digoxin Concentrations by Inhibition of Intestinal P‐Glycoprotein‐Mediated Secretion , 2000, Journal of clinical pharmacology.

[38]  H. Mabuchi,et al.  Effects of NK-104, a new hydroxymethylglutaryl-coenzyme reductase inhibitor, on low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia. Hokuriku NK-104 Study Group. , 2000, The American journal of cardiology.

[39]  K. Kaibuchi,et al.  Pitavastatin enhanced BMP-2 and osteocalcin expression by inhibition of Rho-associated kinase in human osteoblasts. , 2001, Biochemical and biophysical research communications.

[40]  E. Wang,et al.  Quantitative distinctions of active site molecular recognition by P-glycoprotein and cytochrome P450 3A4. , 2001, Chemical research in toxicology.

[41]  M. Kitahara,et al.  Cholesterol-lowering Effect of NK-104, a 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitor, in Guinea Pig Model of Hyperlipidemia , 2001, Arzneimittelforschung.

[42]  J. Kojima,et al.  Effect of Biliary Excretion on the Pharmacokinetics of Pitavastatin (NK-104) in Dogs , 2001 .

[43]  J. S. Wang,et al.  Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[44]  M. Kitahara,et al.  Hypolipidemic Effect of NK-104 and Other 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors in Guinea Pigs , 2001, Arzneimittelforschung.

[45]  P. Neuvonen,et al.  Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate , 2001, Clinical pharmacology and therapeutics.

[46]  K. Yokote,et al.  NK‐104, a 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitor, reduces osteopontin expression by rat aortic smooth muscle cells , 2001, British journal of pharmacology.

[47]  H. Fujino,et al.  Simultaneous determination of taxol and its metabolites in microsomal samples by a simple thin-layer chromatography radioactivity assay--inhibitory effect of NK-104, a new inhibitor of HMG-CoA reductase. , 2001, Journal of chromatography. B, Biomedical sciences and applications.

[48]  A. Peyer,et al.  HMG‐CoA reductase inhibitors and P‐glycoprotein modulation , 2001, British journal of pharmacology.

[49]  Y. Fujikawa,et al.  Synthesis and biological evaluations of quinoline-based HMG-CoA reductase inhibitors. , 2001, Bioorganic & medicinal chemistry.

[50]  S. Yusuf.  MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Commentary , 2002 .

[51]  Y. Iwamoto,et al.  HMG-CoA reductase inhibitor decreases small dense low-density lipoprotein and remnant-like particle cholesterol in patients with type-2 diabetes. , 2002, Life sciences.

[52]  T. Kodama,et al.  The effect of statins on mRNA levels of genes related to inflammation, coagulation, and vascular constriction in HUVEC. Human umbilical vein endothelial cells. , 2002, Journal of atherosclerosis and thrombosis.

[53]  H. Fujino,et al.  Metabolic fate of pitavastatin, a new inhibitor of HMG-CoA reductase--effect of cMOAT deficiency on hepatobiliary excretion in rats and of mdr1a/b gene disruption on tissue distribution in mice. , 2002, Drug metabolism and pharmacokinetics.

[54]  P. Neuvonen,et al.  Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[55]  J. Sasaki,et al.  A randomized, double-blind trial comparing the efficacy and safety of pitavastatin versus pravastatin in patients with primary hypercholesterolemia. , 2002, Atherosclerosis.

[56]  T. Sudhop,et al.  Pharmacology of 3‐Hydroxy‐3‐Methylglutaryl‐Coenzyme A Reductase Inhibitors (Statins), Including Rosuvastatin and Pitavastatin , 2002, Journal of clinical pharmacology.

[57]  Satomi Abe,et al.  Inhibition of migration and proliferation of rat vascular smooth muscle cells by a new HMG-CoA reductase inhibitor, pitavastatin. , 2002, Hypertension research : official journal of the Japanese Society of Hypertension.

[58]  R. Paoletti,et al.  Safety considerations for statins , 2002, Current opinion in lipidology.

[59]  B. Ma,et al.  Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[60]  B. Ma,et al.  Mechanistic studies on metabolic interactions between gemfibrozil and statins. , 2002, The Journal of pharmacology and experimental therapeutics.

[61]  P. Macfarlane,et al.  Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial , 2002, The Lancet.

[62]  J. Sasaki,et al.  Clinical Efficacy of Pitavastatin, a New 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor, in Patients with Hyperlipidemia , 2002, Arzneimittelforschung.

[63]  AndrewJ. S. Coats.  MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebocontrolled trial , 2002, The Lancet.

[64]  P. Neuvonen,et al.  Gemfibrozil greatly increases plasma concentrations of cerivastatin , 2002, Clinical pharmacology and therapeutics.

[65]  M. Kitahara,et al.  Triglyceride-lowering effect of pitvastatin in a rat model of postprandial lipemia , 2002 .

[66]  Y. Tanigawara,et al.  Simvastatin and lovastatin, but not pravastatin, interact with MDR1 , 2002, The Journal of pharmacy and pharmacology.

[67]  H. Mabuchi,et al.  Long-term treatment with pitavastatin (NK-104), a new HMG-CoA reductase inhibitor, of patients with heterozygous familial hypercholesterolemia. , 2002, Atherosclerosis.

[68]  H. Fujino,et al.  Metabolic fate of pitavastatin, a new inhibitor of HMG-CoA reductase: human UDP-glucuronosyltransferase enzymes involved in lactonization , 2003, Xenobiotica; the fate of foreign compounds in biological systems.

[69]  Y. Yonemitsu,et al.  Plaque-stabilizing effect of pitavastatin in Watanabe heritable hyperlipidemic (WHHL) rabbits. , 2003, Journal of atherosclerosis and thrombosis.

[70]  M. Hirano,et al.  INTERACTION BETWEEN FIBRATES AND STATINS - METABOLIC INTERACTIONS WITH GEMFIBROZIL , 2003, Drug metabolism and drug interactions.

[71]  H. Fujino,et al.  Interaction between Several Medicines and Statins , 2003, Arzneimittelforschung.

[72]  M. Kitahara,et al.  Triglyceride-lowering effect of pitavastatin in a guinea pig model of postprandial lipemia. , 2011, Arzneimittel-Forschung.

[73]  J. Kamei,et al.  Pitavastatin inhibits vascular smooth muscle cell proliferation by inactivating extracellular signal-regulated kinases 1/2. , 2003, Journal of atherosclerosis and thrombosis.

[74]  P. Thompson,et al.  Statin-associated myopathy. , 2003, JAMA.

[75]  E. Wang,et al.  HMG-CoA Reductase Inhibitors (Statins) Characterized as Direct Inhibitors of P-Glycoprotein , 2001, Pharmaceutical Research.

[76]  J. Slattery,et al.  Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). 1994. , 1994, Atherosclerosis. Supplements.