• Atorvastatin is a synthetic, selective reversible competitive inhibitor of HMG-CoA reductase, the enzyme that catalyzes the irreversible, rate-limiting reaction in which 3-hydroxy-3-methyl glutaryl-coenzyme A (HMG-CoA) is converted to mevalonate, a precursor of sterols, including cholesterol.
• Atorvastatin is indicated, in conjunction with dietary restriction, in the management of hyperlipidemia. In large, comparative trials atorvastatin produced greater reductions in TC, LDL-C, apo B, and TGs than lovastatin, pravastatin, or simvastatin. About 90% of the maximum observed reductions in LDL are attained with the 1^st two weeks of therapy. Because of the marked reductions in TC and LDL obtained with atorvastatin, this agent may be particularly useful in the treatment of pts with familial hypercholesterolemia (type IIa). Also, because of the added TG-lowering effect, atorvastatin appears to be the ideal choice for the management of mixed dyslipidemia (combined familial hyper-lipoproteinemia; type IIb). Atorvastatin is also useful in the treatment of patients with homozygous familial hypercholesterolemia.
• Experimental evidence suggests that the LDL lowering effect of atorvastatin is mediated by an increased number of LDL receptors on the surface of hepatic cells, leading to enhanced clearance of LDL. The mechanism for TG-lowering effect is less clear, but it may also be related to the low intracellular cholesterol concentration and the inability of the liver to assemble VLDL.
• Currently, there are no published clinical studies that establish the benefits of atorvastatin therapy on morbidity and mortality in hyperlipidemic patients with or without coronary artery disease. Thus, at the present, the evaluation of the clinical efficacy of atorvastatin is based solely on its impressive lipid-lowering ability.

Pharmacokinetics of Atorvastatin

• It is rapidly absorbed and peak plasma level occurs at ~2.5 hrs
• Due to extensive first-pass metabolism, the bioavailability of the parent drug is ~12% and it is not significantly affected by food. However, the bioavailability of HMG-CoA reductase inhibitory activity is ~ 30%
• Atorvastatin is >98% bound to plasma proteins and is extensively metabolized by cytochrome P450 3A4 to active metabolites, which account for about 70% of the circulating HMG-CoA reductase inhibitory activity.
• Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however the drug does not appear to undergo enterohepatic re-circulation.
• Mean plasma elimination half-life is ~ 14 hrs, but because the contribution of active metabolites, the half-life of HMG-CoA reductase inhibitory activity is ~24 hrs
• Atorvastatin metabolism appears to be slower in the elderly, resulting in greater bioavailability and longer half life. However, these changes have little influence on the lipid-lowery effect. No dosage adjustment is necessary.
• Since the kidney plays no role in the disposition of atorvastatin, dosage adjustment in patients with renal impairment is not necessary.
• Patients with hepatic disease may not be able to clear the drug effectively. Atorvastatin is contraindicated in active liver disease or unexplained persistent elevations of serum transaminases.
• The drug dose rather than its plasma level correlates better with LDL reduction. Individualization of drug dose should be based on therapeutic response.

Side Effects of Atorvastatin

• Atorvastatin is generally well-tolerated, adverse reactions have been mild and transient. In
• In controlled clinical studies of 2502 patients, < 2% of patients had to discontinue atorvastatin therapy due to adverse effects.
• Most frequent were constipation, flatulence, dyspepsia, and abdominal pain.

Toxicity

• An animal study demonstrated that even at maternally toxic doses, atorvastatin lacks teratogenicity. However, HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers.
• Atorvastatin, like other HMG-CoA reductase inhibitors, have been associated with abnormal liver function values. Persistent elevations (>3 x upper limit of normal occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trial. It is recommended that liver function tests be performed before the initiation of treatment, at 6 and 12 weeks after initiation of therapy or an increase in dose, and periodically (semiannually) thereafter. Liver enzyme changes generally occur in the first 3 months of treatment with atorvastatin. Patients who develop increased transan6nase levels should be monitored until the abnormalities resolve. Should an increase in ALT or AST of >3 times the upper limit of normal persist, reduction of dose or withdrawal of atorvastatin is recommended. Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
• Rhabdomyolysis with acute renal failure secondary to myoglobinuria has been reported with other drugs in this class.
• Uncomplicated myalgia has been reported in atorvastatin-treated patients
• Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
• Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (severe acute infection, hypotension, major surgery, trauma, severe metabolic / endocrine disorders, and poorly controlled tonic-clonic seizure disorder, etc).

Drug Interactions

• Concurrent use of atorvastatin and drugs that may interfere with its metabolism (Cytochrome P450 3A4) or its protein binding like erythromycin, azole antifungals (e.g. ketoconazole or fluconazole), cyclosporine, gemfibrozil, or niacin may increase serum concentrations of atorvastatin and the risk of myopathy.
• Concurrent use of atorvastatin may increase digoxin serum concentrations

Dosage of Atorvastatin

Atorvastatin (Lipitor®) is available as white, film-coated 10, 20, 40, and 80 mg tablets.

The following points are valid for hypercholesterolemia, mixed dyslipidemia, and homozygous familial hypercholesterolemia. However, for the latter, atorvastatin should be part of a combination regimen of lipid-lowering drugs (and other non-pharmacologic interventions):

• Initial dose: 10 mg once daily;
• Range: 10 to 80 mg once daily, and can be given as a single dose.
• Dose can be given at any time of the day with or without food.
• Dose should be changed based on the observed response and the goal of therapy.
• The NCEP expert panel suggests using LDL level as the primary guide for therapy.
• Recent studies (the "Curves" study) further demonstrate the lipid-lowering superiority of atorvastatin compared to other members of its class. However, the results of this study indicate that doubling the dose from 40 to 80 mg is associated with only a very modest additional reductions in LDL cholesterol. Therefore, the 80 mg dose should be reserved for intractable cases.
• After initiation and/or upon titration of atorvastatin , lipid profile should be analyzed within 4 weeks and dosage adjusted accordingly.

• Atorvastatin vs Placebo (Nawrocki JW et al; Ateriosc. Thromb. Vasc Biol, '95)
  • Comparison with placebo in a 6-week double-blind, placebo-controlled study involving 81 pts with hypercholesterolemia:
  • HDL-cholesterol increased with atorvastatin in a dose-independent fashion to 12%.
  • About 90% of maximum LDL reduction occurred within the first two weeks of treatment

  Dose, mg	placebo	2.5	5	10	20	40	80
  LDL, %	+8	-25	-29	-41	-43	-50	-61
  TG, %	-1	-10	-25	-14	-33	-25	-27

• Atorvastatin vs Simvastatin (Best et al. Abstract '96)
  • After a dietary baseline period of 6 wks, pts were randomized to either atorva or simva (10 mg hs for both)
  • Pts started off with similar baseline lipid profiles, and were treated for one year.
  • The dose was doubled after 16 wks if the pt's LDL was still 130 mg/dL. This occurred more frequently in the simvastatin group.
  • Both at 16 and 52 wks greater reductions in TG, TC, LDL, & apoB were achieved with atorva than with simva. There was no significant difference in their effect on HDL level.
  • Both drugs were well tolerated.

• Atorvastatin vs lovastatin (Bakker-Arkema et al ; Abstract '96)
  • pts with similar baseline lipid profiles (average TC: 275, LDL-C: 190, HDL-C: 49, TG: 180, apoB: 177)
  • Treated for one yr with either atorvastatin 10 mg or lovastatin 20 mg
  • The dose was doubled after 22 wks if the pt's LDL was still above the NCEP target level.
  • After 16 weeks of treatment, all lipid changes except HDL were significantly greater with atorvastatin than with lovastatin :
  • Both drugs were well tolerated. Incidence of persistent ALT elevations was similar for atorvastatin and lovastatin (0. 1% vs 1.2)

  Drug	TC	LDL	TG	apoB
  Atorva	-27	-36	-17	-28
  Lova	-19	-27	-6	-20

• Atorvastatin vs Pravastatin (Egros et al ; Abstract '96)
  • 299 pts with similar baseline lipid profiles (average TC: 288, LDL: 195, HDL: 52)
  • Treated for one yr with either atorvastatin 10 mg or pravastatin 20 mg
  • The dose was doubled after 16 wks if the pt's LDL was still above the NCEP target level.
  • All lipid changes except HDL were significantly greater with atorvastatin than with pravastatin :
  • Both drugs were well tolerated.
  • A similar study confirmed these findings and showed in addition that over 70% of the pts receiving atorva achieved their LDL target level vs only 26% of those receiving pravastatin.

  Drug	TC	LDL	TG	apoB
  Atorvastatin	-25	-35	-17	-27
  Pravastatin	-17	-23	-9	-16

• Atorvastatin vs Niacin (McCormick et al)
  • 108 pts with TC>200 and TG = 200 - 800 received either niacin 1 g tid or atorva 10 mg qd.

  Drug	TG	LDL
  Atorvastatin	-17	-30
  Niacin	-29	-2

• Atorvastatin vs Finofibrate (Hinonen et al)
  • 98 pts (TC>200 and TG > 210) received either fenofibrate 100 mg tid or atorva 10 mg qd.
  • Atorva was more effective in lowering TC (-23% vs +6 %) and less effective in lowering TG (- 26% vs - 48%)

• Atorvastatin (80 mg qd) vs Atorvastatin (40 mg qd) plus colistipol (10 g bid) (Hinonen et al)
  • 189 pts with severe hypercholesterolemia(TC>200 and TG > 210) received either fenofibrate 100 mg tid or atorva 10 mg qd.

    Treatment	TC	LDL	LDH	TC
    Atorva 80 mg qd	-43	-52	+7	-33
    Atorva 40 mg qd + Colistipol	-42	-53	+9	-17

• CURVES is an 8-wk multicenter, open-label, randomized, comparative-dose safety and efficacy study of qd atorvastatin compared with simvastatin, lovastatin, pravastatin, and fluvastatin.
• 6 wks dietary baseline period (LDL 160 and TG 400 mg/dL) were followed by 8 wks of treatment.
• A total of 505 pts were involved in the study. Sample sizes were predetermined to show statistically significant differences in LDL reduction between mg-equivalent doses of each treatment group. Pt demographics was similar between groups. Mean age was 55 yrs; average BMI = 26.7 (Kg/m²); 37% of pts had a family history of CHD; 13% were smokers

  	Number of pts per treatment arm
  	10 mg	20 mg	40 mg	80 mg
  Atorvastatin	74	52	62	10 (80 qd)
  Simvastatin	74	51	62	0
  Pravastatin	74	43	25	0
  Lovastatin	0	16	16	11 (40 bid)
  Fluvastatin	0	12	12	0

• At a 10-mg dose, atorvastatin reduced LDL significantly more than 10 mg simvastatin, 20 mg & 40 mg lovastatin, 20 mg pravastatin, and 20 mg & 40 mg fluvastatin
• At 20-mg dose, atorvastatin reduced LDL significantly more than 20 mg or 40 mg simvastatin, and 40 mg pravastatin.
• At the usual first titrations (doubling of the initial dosage), atorvastatin demonstrated significantly greater LDL reductions that other statins (see figure below)
• All statins were well tolerated and there were no significant differences in the incidence of side effects among the different statins.

Figure 1 Results of the CURVES trial, a multicenter clinical investigation that evaluated the safety and efficacy of comparative doses of five HMG-CoA reductase inhibitors (sponsered by Parke-Davis and Pfizer; 11/1997).

• Atorvastatin is an HMG-reductase inhibitor indicated in the management of hypercholesterolemia (LDL) or mixed hyperlipidemia (LDL & TG).
• It is given once a day (with or without food at any time of the day). The dose ranges from 10 to 80 mg , depending on the severity of the condition and the pt's response. The highest dose should be reserved for severe cases.
• Atorvastatin is the only HMG-reductase inhibitor capable of significantly reducing both cholesterol and triglycerides in hyperlipidemic patients. It has the highest lipid-lowering capacity of all agents in its class.
• Atorvastatin has an excellent safety profile, comparable to that of other statins. Liver function tests should be obtained at 6 wks, 12 wks, and then every 3 to 6 months and whenever the dose is raised.. Pts should be aware of the signs of myositis or myopathy, which occur rarely in pts receiving statins (and other lipid-lowering drugs).
• Atorvastatin may be regarded as the HMG-CoA reductase inhibitor of choice for patients with heterozygous familial hypercholesterolemia.
• Clinical studies suggest that tatients treated with atorvastatin are more likely to attain their NCEP LDL target level than those treated with other statins.
• Atorvastatin may be the most useful statin in the treatment of patients with homozygous familial hypercholesterolemia who may require pheresis in addition to drug therapy.
• Atorvastatin significantly reduces TG levels in patients with hypertriglyceridemia or combined hyperlipidemia. For the latter group of pts, atorvastatin is clearly the statin of choice since it is the only statin capable of reducing both LDL and TG.
• Atorvastatin achieves greater reductions in TC and LDL than niacin or fibric acid derivatives. However, these agents produced larger reductions in TG levels.
• In certain kinds of hyperlipidemia, a combination of atorvastatin and niacin or a fibric acid derivative is often required. In these cases, patients should be closely monitored for signs of myopathy and liver dysfunction.
• A major multicenter study in four continents is currently evaluating the benefits of atorvastatin (10 mg qd) in 2250 elderly patients (>65 yrs) with NIDDM. It is noteworthy that about 70% of hospital admissions of diabetic pts are attributable to some cardiovascular problem related to atherosclerosis.

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