DIMITROL 4

Indications

• Hyperlipidemia
• Dyslipidemia
• Primary prevention of cardiovascular disease
• Secondary prevention of cardiovascular events

Dosage

Adults: The typical adult dosage of pitavastatin is 1 to 4 mg once daily

Mechanism of action

Pitavastatin inhibits HMG-CoA reductase, the enzyme responsible for converting HMG-CoA to mevalonate, a precursor in cholesterol synthesis. This inhibition leads to decreased cholesterol production in the liver, which in turn stimulates the upregulation of hepatic LDL receptors. The increased uptake of LDL by the liver results in reduced circulating levels of LDL-C. Additionally, pitavastatin exhibits pleiotropic effects, enhancing endothelial function, stabilizing atherosclerotic plaques, reducing oxidative stress and inflammation, and inhibiting thrombogenic responses.

Pharmacodynamics

Pitavastatin is an oral antilipemic agent that effectively lowers total cholesterol, LDL-C, apolipoprotein B (apoB), non-HDL-C, and triglyceride levels while increasing HDL-C concentrations. Elevated LDL-C, low HDL-C, and high triglycerides are associated with an increased risk of atherosclerosis and cardiovascular disease. By improving lipid profiles, pitavastatin reduces cardiovascular morbidity and mortality and is recognized for its cost-effectiveness in treating cardiovascular diseases.

Pharmacokinetics

Pitavastatin is well-absorbed following oral administration, with peak plasma concentrations typically occurring within 1 to 4 hours. It is metabolized primarily in the liver via the cytochrome P450 system, particularly CYP2C9 and CYP2C19. The elimination half-life of pitavastatin is approximately 12 hours, and it is excreted mainly in the feces, with a smaller percentage excreted in urine. Its pharmacokinetics can be affected by factors such as liver function and interactions with other medications.

Contra-indications

• Active liver disease
• Pregnancy
• Breastfeeding
• Hypersensitivity to pitavastatin or any of its components

Adverse effects

• Myopathy
• Rhabdomyolysis
• Elevated liver enzymes
• Gastrointestinal disturbances (e.g., constipation, diarrhea, abdominal pain)
• Headache
• Dizziness
• Fatigue

Interactions

• Coadministration with strong CYP3A4 inhibitors (e.g., ketoconazole, erythromycin) may increase risk of myopathy
• Certain anticoagulants (e.g., warfarin) may have altered effects
• Other lipid-lowering agents may increase risk of myopathy when used concurrently

Precautions

• Monitor liver function tests before and during therapy
• Use with caution in patients with a history of liver disease
• Assess muscle symptoms regularly, especially in elderly patients or those with renal impairment
• Avoid excessive alcohol consumption

Pregnancy

Pitavastatin is contraindicated in pregnancy due to potential harm to the fetus and lack of safety data.

Breast-feeding

Pitavastatin is contraindicated during breastfeeding, as it may pass into breast milk and affect the nursing infant.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Pitavastatin 1 mg tablet
• Pitavastatin 4 mg tablet
• Pitavastatin 2 mg tablet

Mechanism of action

Pitavastatin is a statin medication and a competitive inhibitor of the enzyme HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Pitavastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increase hepatic uptake of LDL, thereby reducing circulating LDL-C levels. In vitro and in vivo animal studies also demonstrate that statins exert vasculoprotective effects independent of their lipid-lowering properties, also known as the pleiotropic effects of statins. This includes improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response. Statins have also been found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an important role in leukocyte trafficking and in T cell activation. Hepatic ATP-binding cassette transporter A1 (ABCA1) plays a key role in high-density lipoprotein (HDL) production by apolipoprotein A-I (ApoA-I) lipidation. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, increase ABCA1 mRNA levels in hepatoma cell lines ... . We investigated how statins increase ABCA1 in rat hepatoma McARH7777 cells. Pitavastatin, atorvastatin, and simvastatin increased total ABCA1 mRNA levels, whereas pravastatin had no effect. Pitavastatin also increased ABCA1 protein. Hepatic ABCA1 expression in rats is regulated by both liver X receptor (LXR) and sterol regulatory element-binding protein (SREBP2) pathways. Pitavastatin repressed peripheral type ABCA1 mRNA levels and its LXR-driven promoter, but activated the liver-type SREBP-driven promoter, and eventually increased total ABCA1 mRNA expression. Furthermore, pitavastatin increased peroxisome proliferator-activated receptor a (PPARa) and its downstream gene expression. Knockdown of PPARa attenuated the increase in ABCA1 protein, indicating that pitavastatin increased ABCA1 protein via PPARa activation, although it repressed LXR activation. Furthermore, the degradation of ABCA1 protein was retarded in pitavastatin-treated cells. These data suggest that pitavastatin increases ABCA1 protein expression by dual mechanisms: SREBP2-mediated mRNA transcription and PPARa-mediated ABCA1 protein stabilization, but not by the PPAR-LXR-ABCA1 pathway. Pitavastatin competitively inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is a rate-determining enzyme involved with biosynthesis of cholesterol, in a manner of competition with the substrate so that it inhibits cholesterol synthesis in the liver. As a result, the expression of low-density lipoprotein (LDL)-receptors followed by the uptake of LDL from blood to liver is accelerated and then the plasma total cholesterol (TC) decreases. Further, the sustained inhibition of cholesterol synthesis in the liver decreases levels of very low density lipoproteins. Statin use in individuals with chronic obstructive pulmonary disease (COPD) with coexisting cardiovascular disease is associated with a reduced risk of exacerbations. ... To explore the mechanisms involved, we investigated the effect of statin on endothelial cell function, especially endothelial cell tight junctions. We primarily assessed whether pitavastatin could help mitigate the development of emphysema induced by continuous cigarette smoking (CS) exposure. We also investigated the activation of liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling, which plays a role in maintaining endothelial functions, important tight junction proteins, zonula occludens (ZO)-1 and claudin-5 expression, and lung microvascular endothelial cell permeability. RESULTS: We found that pitavastatin prevented the CS-induced decrease in angiomotin-like protein 1 (Amot

Pharmacodynamics

Pitavastatin is an oral antilipemic agent which inhibits HMG-CoA reductase. It is used to lower total cholesterol, low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apoB), non-high density lipoprotein-cholesterol (non-HDL-C), and trigleride (TG) plasma concentrations while increasing HDL-C concentrations. High LDL-C, low HDL-C and high TG concentrations in the plasma are associated with increased risk of atherosclerosis and cardiovascular disease. The total cholesterol to HDL-C ratio is a strong predictor of coronary artery disease and high ratios are associated with higher risk of disease. Increased levels of HDL-C are associated with lower cardiovascular risk. By decreasing LDL-C and TG and increasing HDL-C, rosuvastatin reduces the risk of cardiovascular morbidity and mortality. Elevated cholesterol levels, and in particular, elevated low-density lipoprotein (LDL) levels, are an important risk factor for the development of CVD. Use of statins to target and reduce LDL levels has been shown in a number of landmark studies to significantly reduce the risk of development of CVD and all-cause mortality. Statins are considered a cost-effective treatment option for CVD due to their evidence of reducing all-cause mortality including fatal and non-fatal CVD as well as the need for surgical revascularization or angioplasty following a heart attack. Evidence has shown that even for low-risk individuals (with <10% risk of a major vascular event occurring within 5 years) statins cause a 20%-22% relative reduction in major cardiovascular events (heart attack, stroke, coronary revascularization, and coronary death) for every 1 mmol/L reduction in LDL without any significant side effects or risks. **Skeletal Muscle Effects** Pitavastatin may cause myopathy (muscle pain, tenderness, or weakness with creatine kinase (CK) above ten times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria). Rare fatalities have occurred as a result of rhabdomyolysis with statin use, including pitavastatin. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. As dosages of pitavastatin greater than 4mg per day were associated with an increased risk of severe myopathy, the product monograph recommends a maximum daily dose of 4mg once daily. The risk of myopathy during treatment with pitavstatin may be increased with concurrent administration of interacting drugs such as [fenofibrate], [niacin], [gemfibrozil], and [cyclosporine]. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with [colchicine], and caution should therefore be exercised when prescribing these two medications together. Real-world data from observational studies has suggested that 10-15% of people taking statins may experience muscle aches at some point during treatment. **Hepatic Dysfunction** Increases in serum transaminases have been reported with pitavastatin. In most cases, the elevations were transient and either resolved or improved on continued therapy or after a brief interruption in therapy. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pitavastatin. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. **Increases in HbA1c and Fasting Serum Glucose Levels** Increases in HbA1c and fasting serum glucose levels have been reported with statins, including pitavastatin. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices. An in vitro study found that [atorvastatin], [pravastatin], [rosuvastatin], and [pitavastatin] exhibited a dose-dependent cy