Statin-Induced Myotoxicity: Pharmacokinetic Differences among Statins and the Risk of Rhabdomyolysis, with Particular Reference to Pitavastatin

Abstract

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the most widely prescribed therapeutic class of drugs worldwide, with established clinical benefits both in terms of improving serum lipid profiles and reducing cardiovascular events and mortality. Although statins have a favorable risk-to-benefit ratio, they have the potential to cause adverse events which can result in muscular inflammation (myositis), muscle breakdown (rhabdomyolysis) and, ultimately, kidney failure. While the incidence of rhabdomyolysis is approximately 3.4 cases per 100,000 person-years with standard-dose statin therapy, the risk of developing the condition increases substantially at higher therapeutic doses. This effect may be exacerbated by prescribing statins in combination with certain other medications because drug � drug interactions increase statin exposure by interacting with enzymes that would normally be involved in their metabolism and clearance. Co-administration of drugs that inhibit the cytochrome P450 (CYP) enzymes responsible for metabolizing statins, or that interact with the organic anion-transporting polypeptides (OATPs) responsible for statin uptake into hepatocytes, substantially increases the risk of developing myotoxicity. Such effects vary among statins according to their metabolic profile. For example, pitavastatin, a novel statin approved for the treatment of hypercholesterolemia and combined (mixed) dyslipidemia, is not catabolized by CYP3A4, unlike other lipophilic statins, and may be less dependent on the OATP1B1 transporter for its uptake into hepatocytes before clearance. Such differences in drug � drug interaction profiles among available statins offer the possibility of reducing the risk of myotoxicity among high-risk patients.

Disadvantages of Current LDL-cholesterol Lowering and the Role of PCSK9 Inhibitors.

“…18-20 te da se kod nekih statina (pravastatina, fluvastatina i pitavastatina) zbog različitih putova metabolizma, mišićne nuspojave pojavljuju rjeđe 21, 22 . Nedavna istraživanja upućuju na mogućnost postizanja tolerancije statina u većine bolesnika koji ih ne podnose smanjenjem doze i intermitentnom primjenom lijeka 23, 24 .…”

“…and that muscle side effects are more rare for some statins (pravastatin, fluvastatin, and pitavastatin) due to different metabolic pathways 21,22 . Recent studies indicate the possibility of achieving statin tolerance in most patients with statin intolerance through dose reduction and intermittent drug application 23, 24 .…”

Comparison of Scaled-average, Population, and Individual Bioequivalence on 2 Tablets of Pitavastatin Calcium: A 3-Period, Reference-replicated, Crossover Study in Healthy Chinese Volunteers

“…[8][9][10] Most of the HMG-CoA reductase inhibitors (statins) were categorized as highly variable according to the collected data from in vivo bioequivalence (BE) studies at US Food and Drug Administration's (FDA's) Office of Generic Drugs. 10,11 By definition, a drug or drug product was considered highly variable if the root mean square error for C max and/or AUC was 430%. 12 A number of factors can result in high variability, such as physiologic (gastrointestinal motility and secretions), physicochemical (products' batch-to-batch similarity), and pathologic conditions of the individuals studied and any drug-related issues (presystemic metabolism).…”

Short-Term Effect of Pitavastatin Treatment on Glucose and Lipid Metabolism and Oxidative Stress in Fasting and Postprandial State Using a Test Meal in Japanese Men

“…Pitavastatin, a member of the medication class of statins, has been available in the market in Japan since 2003. It has been well recognized that this statin is markedly effective in reducing low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and increasing high-density lipoprotein cholesterol (HDL-C), while it is scarcely metabolized by hepatic drug-metabolizing enzymes cytochrome P450 (CYP) [16–21]. As a consequence, pitavastatin is most likely to be appropriate for patients with metabolic syndrome with high LDL, low HDL, and diabetes mellitus.…”