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.
Pitavastatin (pi ta" va stat' in) is a potent, orally available inhibitor of hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase the major rate limiting enzyme in cholesterol synthesis. Like other members of its class (the “statins”), pitavastatin lowers total serum cholesterol and low density lipoprotein (LDL) concentrations, thereby reducing the risk of atherosclerosis and its complications – myocardial infarction and stroke. Pitavastatin was approved for use in the United States in 2009 but experience with its use is limited. Pitavastatin is indicated for treatment of hypercholesterolemia in persons at high risk for coronary, cerebrovascular and peripheral artery disease. Pitavastatin is available in tablets of 1, 2 and 4 mg under the trade name Livalo. Pitavastatin is one of the more potent statins and is typically used in a comparably lower dose. The recommended dose is 2 to 4 mg once daily based upon tolerability and lipid levels. Common side effects include muscle cramps, joint aches, headache and weakness.
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.
Likelihood score: D (possible rare cause of clinically apparent liver injury).
Mechanism of Injury
The cause of hepatic injury from pitavastatin is unknown. Pitavastatin is minimally (~10%) metabolized in the liver (via CYP 2C9). The mild, self-limited ALT elevations may be due to a toxic intermediate of drug metabolism and the reversal of these elevations due to adaptation. The idiosyncratic, clinically apparent liver injury associated with many statins is often accompanied by autoimmune features and may, therefore, be caused by immune mechanisms.
Outcome and Management
The mild ALT elevations associated with pitavastatin therapy are usually self-limited and do not require dose modification. Pitavastatin should be stopped if ALT levels rise above 10-fold the ULN, or persist in being above 5-fold elevated or are associated with symptoms. In the clinically apparent liver injury attributed to statins, recovery is usually complete within 1 to 2 months. Recurrence of injury with rechallenge has been reported and should be avoided. Whether there is cross relativity to hepatic injury with other statins is unknown.
REPRESENTATIVE TRADE NAMES
Pitavastatin – Livalo®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 05 August 2017
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