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Atosta 5/10/20 Atosta Systematic (IUPAC) name (3R,5R)-7-[2-(4-fluorophenyl)3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)- 1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid Pharmacokinetic data Bioavailability Metabolism 12% Hepatic - CYP3A4 Half-life 14 h Excretion Bile Therapeutic considerations Routes oral Atosta is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms. Like all statins, Atosta works by inhibiting HMG-CoA reductase, an enzyme found in liver tissue that plays a key role in production of cholesterol in the body. Clinical use Indications Hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa and IIb) to reduce total cholesterol, LDL-C, apo-B, Triglycerides levels, and CRPas well as increase HDL levels. Heterozygous familial hypercholesterolemia in pediatric patients Homozygous familial hypercholesterolemia Hypertriglyceridemia (Fredrickson Type IV) Primary dysbetalipoproteinemia (Fredrickson Type III) It has also been used in the treatment of combined hyperlipidemia. Secondary prophylaxis in patients with coronary heart disease and multiple risk factors for myocardial infarction, stroke, unstable angina, and revascularization. Myocardial infarction and stroke prophylaxis in patients with type II diabetes. Concomitant therapy considerations Atosta may be used in combination with bile acid resins. It is not recommended to combine statin treatment with fibrates because of the increased risk of myopathy related adverse reactions. Drug dose must be adjusted according to age of patient, and must be lowered in Hepatic insufficiency Contraindications Active liver disease: cholestasis, hepatic encephalopathy, hepatitis, and jaundice Unexplained elevations in AST or ALT levels Pregnancy Breast-feeding Precaution must be taken when treating with Atosta, because rarely it may lead to rhabdomyolysis it may be very serious leading to acute renal failure due to myoglobinuria. If rhabdomyolysis is suspected or diagnosed, Atosta therapy should be discontinued immediately. Also Atosta should be discontinued if a patient has markedly elevated CPK levels or if a myopathy is suspected or diagnosed. The likelihood of developing a myopathy is increased by the co-administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, and azole antifungals. Atosta is absolutely contraindicated in pregnancy, it is likely to cause harm to fetal development because of the importance of cholesterol and various products in the cholesterol biosynthesis pathway for fetal development, including steroid synthesis and cell membrane production. It is not recommended that nursing mothers take Atosta due to the possibility of adverse reactions in nursing infants, since experiments with rats indicate that Atosta is likely to be secreted into human milk.[18] Atosta tablets are marketed in tablets (5,10, 20 mg) for oral administration Adverse effects As stated earlier, myopathy with elevation of creatinine kinase (CK) and rhabdomyolysis are the most serious, although rare <1%. Headache is the most common side effect, occurring in more than 10% of patients. Side effects that occur in 1-10% of patients taking Atosta include: Weakness Insomnia and dizziness. Chest pain and peripheral edema Rash Abdominal pain, constipation, diarrhoea, dyspepsia, flatulence, nausea Urinary tract infection Arthralgia, myalgia, back pain, arthritis Sinusitis, pharyngitis, bronchitis, rhinitis Infection, flu-like syndrome, allergic reaction. Atosta, and other statins, are associated with anecdotal reports of memory loss by consumers which have been seen in clinical practice in a tiny percentage of users, particularly women. Evidence is conflicting with anecdotal reports contrasting with a well established association of high cholesterol with dementia. However, it is known that cholesterol synthesis is necessary for normal neuron functioning. Elevation of alanine transaminase (ALT) and aspartate transaminase (AST) has been described in a few cases Drug and food interactions Interactions with clofibrate, fenofibrate, gemfibrozil, which are fibrates used in accessory therapy in many forms of hypercholesterolemia, usually in combination with statins, increase the risk of myopathy and rhabdomyolysis Co-administration of Atosta with one of CYP3A4 inhibitors like itraconazole, telithromycin and voriconazole, may increase serum concentrations of Atosta, which may lead to adverse reactions. This is less likely to happen with other CYP3A4 inhibitors like diltiazem, erythromycin, fluconazole, ketoconazole, clarithromycin, cyclosporine, protease inhibitors, or verapamil, and only rarely with other CYP3A4 inhibitors like amiodarone and aprepitant. Often bosentan, fosphenytoin, and phenytoin, which are CYP3A4 inducers, can decrease the plasma concentrations of Atosta. But only rarely barbiturates, carbamazepine, efavirenz, nevirapine, oxcarbazepine, rifampin, and rifamycin which are CYP3A4 inducers can decrease the plasma concentrations of Atosta. Oral contraceptives increased AUC values for norethindrone and ethinyl estradiol, these increases should be considered when selecting an oral contraceptive for a woman taking Atosta. Antacids can rarely decrease the plasma concentrations of Atosta but do not affect the LDL-C lowering efficacy. Niacin also is proved to increase the risk of myopathy or rhabdomyolysis Statins may also alter the concentrations of other drugs, such as warfarin or digoxin, leading to alterations in effect or a requirement for clinical monitoring. Vitamin D supplementation lowers Atosta and active metabolite concentrations yet has synergistic effects on cholesterol concentrations. Grapefruit juice components are known inhibitors of intestinal CYP3A4. Co-administration of grapefruit juice with Atosta may cause an increase in Cmax and AUC, which can lead to adverse reactions or overdose toxicity Mechanism of action As with other statins, Atosta is a competitive inhibitor of HMG-CoA reductase. Unlike most others, like the natural polypetide lovastatin, however, it is a completely synthetic compound. HMG-CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) to mevalonate, which is the rate-limiting step in hepatic cholesterol biosynthesis. Inhibition of the enzyme decreases de novo cholesterol synthesis, increasing expression of low-density lipoprotein receptors (LDL receptors) on hepatocytes. This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-cholesterol in the blood. Like other statins, Atosta also reduces blood levels of triglycerides and slightly increases levels of HDL-cholesterol. In clinical trials, drugs that block cholesterol uptake like ezetimibe combine with and complement those that block biosynthesis like Atosta or simvastatin in lowering cholesterol or targeting levels of LDL. Pharmacokinetics Atosta has rapid oral absorption with an approximate time to maximum plasma concentration (Tmax) of 1–2 hours. The absolute bioavailability of Atosta is approximately 14%, however, the systemic availability for HMG-CoA reductase activity is approximately 30%. Atosta undergoes high intestinal clearance and first-pass metabolism, which is the main cause for the low systemic availability. Food has been shown to reduce the rate and extent of Atosta absorption. Administration of Atosta with food produces a 25% reduction in Cmax (rate of absorption) and a 9% reduction in AUC (extent of absorption). However, food does not affect the plasma LDL-C lowering efficacy of Atosta. Evening Atosta dose administration is known to reduce the Cmax (rate of absorption) and AUC (extent of absorption) by 30% each. However, time of administration does not affect the plasma LDL-C lowering efficacy of Atosta. Atosta is highly protein bound (≥98%). The primary proposed mechanism of Atosta metabolism is through cytochrome P450 3A4 hydroxylation to form active ortho- and parahydroxylated metabolites, as well as various beta-oxidation metabolites. The ortho- and parahydroxylated metabolites are responsible for 70% of systemic HMG-CoA reductase activity. The ortho-hydroxy metabolite undergoes further metabolism via glucuronidation. As a substrate for the CYP3A4 isozyme it has shown susceptibility to inhibitors and inducers of CYP 3A4 to produce increased or decreased plasma concentrations, respectively. This interaction was tested in vitro with concurrent administration of erythromycin, a known CYP 3A4 isozyme inhibitor, which resulted in increased plasma concentrations of Atosta. Atosta is also an inhibitor of cytochrome 3A4. It is primarily eliminated via hepatic biliary excretion with less than 2% of Atosta recovered in the urine. Bile elimination follows hepatic and/or extra-hepatic metabolism. There does not appear to be any entero-hepatic recirculation. Atosta has an approximate elimination half-life of 14 h. Noteworthy, the HMG-CoA reductase inhibitory activity appears to have a half-life of 20–30 h, which is thought to be due to the active metabolites. Atosta is also a substrate of the intestinal P-glycoprotein efflux transporter, which pumps the drug back into the intestinal lumen during drug absorption In Hepatic insufficiency, plasma drug concentrations are significantly affected by concurrent liver disease. Patients with A-stage liver disease show a 4-fold increase in both Cmax and AUC. Patients with B-stage liver disease show an 16-fold increase in Cmax and an 11-fold increase in AUC. In geriatric patients (>65 years old) show altered pharmacokinetics of Atosta compared to young adults. The mean AUC and Cmax values are higher (40% and 30%, respectively) for geriatric patients. Additionally, healthy elderly patients show a greater pharmacodynamic response to Atosta at any dose, therefore, this population may have lower effective doses.