Pitavastatin

Pitavastatin is used to lower elevated total cholesterol (TC) and LDL-C levels in: adult patients with primary hypercholesterolemia - including heterozygous familial hypercholesterolemia - and combined (mixed) dyslipidemia when dietary and other non-drug measures do not provide an adequate response.

Compared to other statins, pitavastatin is a highly potent 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor and an efficient inducer of the hepatocyte low-density lipoprotein cholesterol (LDL-C) receptor. Its characteristic structure (heptenoate as the basic structure, a quinoline core ring and side chains containing fluorophenyl and cyclopropyl moieties) provides improved pharmacokinetics and a significant LDL-C lowering effect at low doses. As a result of the inhibition of hepatic cholesterol synthesis, the expression of LDL receptors in the liver is increased. This favors the uptake of circulating LDL from the blood and thus causes a reduction in the concentrations of total cholesterol (TC) and LDL cholesterol (LDL-C). By inhibiting cholesterol synthesis in the liver, VLDL secretion into the blood is reduced, so that the plasma levels of triglycerides (TG) fall.

Absorption: Pitavastatin is rapidly absorbed in the upper gastrointestinal tract and reaches maximum plasma concentrations within one hour after oral administration. Absorption is not affected by concomitant food intake. The unchanged substance is subject to enterohepatic circulation and is well absorbed in the jejunum and ileum. The absolute bioavailability of Pitavastatin is 51 percent.

Distribution: Pitavastatin is more than 99 percent bound to proteins in human plasma. The mean volume of distribution is about 133 liters. Pitavastatin is actively transported by various hepatic uptake transporters, including OATP1B1 and OATP1B3, into hepatocytes, the site of action and metabolism.

Plasma AUC is variable, with the highest value being about 4 times the lowest. According to studies with SLCO1B1 (the gene coding for OATP1B1), the AUC variability could possibly be explained to a large extent by a polymorphism of this gene. Pitavastatin is not a substrate for p-glycoprotein.

Metabolization: In plasma, pitavastatin is predominantly present as an unchanged substance. The main metabolite is the inactive lactone, which is formed by UDP-glucuronosyltransferases (UGT1A3 and 2B7) via a pitavastatin-glucuronide ester conjugate. Pitavastatin is only minimally metabolized via the CYP system: CYP2C9 (and to a lesser extent CYP2C8) is responsible for the metabolism of pitavastatin to minor metabolites.

Excretion: Although unchanged pitavastatin is rapidly excreted from the liver into the bile, it is subject to enterohepatic circulation, so that the duration of action is prolonged accordingly. Less than 5 percent of a pitavastatin dose is eliminated renally. The plasma elimination half-life is between 5.7 (single dose) and 8.9 hours (steady-state) and the geometric mean of the apparent oral clearance is 43.4 l/h after a single dose.

The use of Pitavastatin during pregnancy is contraindicated. Women of childbearing age must use a reliable method of contraception during treatment with pitavastatin. Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of inhibition of HMG CoA reductase outweighs the benefit of treatment during pregnancy. If a pregnancy is planned, treatment should be discontinued at least one month before conception. If a patient becomes pregnant during the use of pitavastatin, treatment must be discontinued immediately.

Lactation: Pitavastatin must not be used during lactation. Pitavastatin passes into the milk of rats. It is not known whether the active substance also passes into breast milk in humans.

The active substance pitavastatin is available on the German market in the form of film-coated tablets in strengths of 1, 2 and 4 mg.

The usual initial dose is 1 mg pitavastatin once/day. Dose adjustments should be made at intervals of at least 4 weeks. The dosage should be individualized according to LDL-C levels, the therapeutic goal and the patient's response to therapy. Most patients require a dose of 2 mg. The maximum daily dose is 4 mg.

Common adverse reactions (≥ 1/100, < 1/10) occurring during treatment with pitavastatin include:

• Headache
• constipation, diarrhea, dyspepsia, nausea
• myalgia, arthralgia

Associations have been suspected between:

• Angioedema: the PRAC believes that a causal link between pitavastatin and angioedema can be established.
• Lupus-like syndrome: there is a reasonable possibility of a causal relationship between pitavastatin and lupus-like syndrome.
• Gynecomastia: there is a reasonable possibility of a causal relationship between pitavastatin and gynecomastia.

Pitavastatin is actively transported into human hepatocytes by various hepatic uptake transporters, including OATP (transport polypeptide for organic anions), which may play a role in some of the interactions mentioned below.

• Ciclosporin: Co-administration of a single dose of ciclosporin with pitavastatin at steady state resulted in a 4.6-fold increase in the AUC of pitavastatin. Pitavastatin is contraindicated in patients treated with ciclosporin.
• Erythromycin: Concomitant administration with pitavastatin resulted in a 2.8-fold increase in the AUC of pitavastatin. Temporary interruption of pitavastatin therapy is recommended for the duration of treatment with erythromycin or other macrolide antibiotics.
• Gemfibrozil and other fibrates: The use of fibrates alone is occasionally associated with myopathy. The concomitant use of fibrates with statins has been associated with increased myopathy and rhabdomyolysis. In pharmacokinetic studies, concomitant administration of pitavastatin and gemfibrozil resulted in a 1.4-fold increase in the AUC of pitavastatin and concomitant administration of with fenofibrate resulted in a 1.2-fold increase in the AUC of pitavastatin.
• Niacin: The use of niacin alone may be associated with myopathy and rhabdomyolysis. Caution is therefore advised with concomitant use with niacin and pitavastatin.
• Fusidic acid: There are reports of serious muscle problems such as rhabdomyolysis, which are attributed to interactions between fusidic acid and statins. Temporary interruption of pitavastatin therapy is recommended for the duration of treatment with fusidic acid.
• Rifampicin: Concomitant administration with pitavastatin resulted in a 1.3-fold increase in the AUC of pitavastatin due to reduced hepatic uptake.
• Protease inhibitors: Minor changes in the AUC of pitavastatin may occur when co-administered with pitavastatin.
• Warfarin: Steady-state pharmacokinetics and pharmacodynamics (INR and prothrombin time) of warfarin were not affected by concomitant administration of 4 mg pitavastatin daily in healthy volunteers. Nevertheless, as with other statins, the prothrombin time or INR value should be monitored in patients treated with warfarin when pitavastatin is also used.

in patients with known hypersensitivity to pitavastatin or other statins

in patients with severe hepatic insufficiency, active liver disease or unexplained persistent increases in serum transaminases (to more than three times the upper normal value)

in patients with myopathy

with concomitant ciclosporin therapy

during pregnancy, while breastfeeding and in women of childbearing age without reliable contraception

In addition to pitavastatin, there are a number of other statins available on the German market that differ in terms of their pharmacokinetics.

• Atorvastatin (t1⁄2 elimination 14 h, CYP3A4)
• Fluvastatin (t1⁄2 elimination 2.3 ± 0.9 h, several CYP450 degradation pathways)
• Lovastatin (t1⁄2 elimination 2 h, CYP3A4)
• Pravastatin (t1⁄2 elimination 1.5-2 h, not via CYP450 system)
• Rosuvastatin (t1⁄2 elimination 19 h, only 10% metabolized, mainly via CYP2C9)
• Simvastatin (t1⁄2 elimination 1.9 h, CYP3A4)

Compared to other statins, pitavastatin is a highly potent 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor and an efficient inducer of the hepatocyte low-density lipoprotein cholesterol (LDL-C) receptor. Its characteristic structure (heptenoate as the basic structure, a quinoline core ring and side chains containing fluorophenyl and cyclopropyl moieties) provides improved pharmacokinetics and a significant LDL-C lowering effect at low doses. Unlike other statins, the cyclopropyl group on the pitavastatin molecule appears to divert the drug from metabolism by cytochrome P450 (CYP) 3 A4, allowing only a small degree of clinically insignificant metabolism by CYP2C9. Therefore, pitavastatin is minimally metabolized; the majority of the bioavailable fraction of an oral dose is excreted unchanged in bile and absorbed by the small intestine ready for enterohepatic recirculation. This process is probably responsible for the increased bioavailability of pitavastatin compared to most other statins and contributes to its prolonged duration of action.

Pitavastatin showed more significant changes in LDL-C, TG and HDL-C compared to baseline in patients with hypercholesterolemia and metabolic syndrome (Saito Y (2011)

Dizziness and drowsiness may occur during treatment with pitavastatin, which may impair your ability to drive and operate machinery!

1. Saito Y (2011) Pitavastatin: an overview. Atheroscler Suppl 12:271-276.