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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.
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Clinical use
Indications
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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.
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Heterozygous familial hypercholesterolemia in pediatric patients
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Homozygous familial hypercholesterolemia
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Hypertriglyceridemia (Fredrickson Type IV)
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Primary dysbetalipoproteinemia (Fredrickson Type III)
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It has also been used in the treatment of combined hyperlipidemia.
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Secondary prophylaxis in patients with coronary heart disease and multiple risk
factors for myocardial infarction, stroke, unstable angina, and revascularization.
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Myocardial infarction and stroke prophylaxis in patients with type II diabetes.
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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
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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%.
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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:
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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.