Study Fluvastatin

Fluvastatin, launched in 1994, was the first S5mthetic HMG-CoA reductase inhibitor to be approved for the treatment of hypercholesterolemia. This statin was developed by Novartis (Sandoz), and it is marketed as a racemate under the trade name Lescol (Asberg and Holdaas, 2004). In laboratory studies, fluvastatin was shown to potently inhibit HMG-CoA reductase (IC50 = 8 nM) and effectively block cholesterol biosynthesis in hepatoc5de cells (IC50 = 52 nM) (Parker et al., 1990). Clinically, fluvastatin is prescribed less frequently than simvastatin, atorvastatin, or rosuvastatin, but it nevertheless remains an important medication for the treatment of hypercholesterolemia moreover, as the first completely S5mthetic statin to be approved, it offers a compelling synthetic story (Repic et al., 2001). 

Despite these marked reductions in fluvastatin bioavailability, other studies in large numbers of hypercholesterolaemic patients have shown that concurrent use actually has additive lipid-lowering effects.In the first of these studies, fluvastatin was given 4 hours after coiestyramine, but the other study did not indicate whether or not doses were separated. ... 

Renal function impairment- Dose adjustments for mild to moderate renal impairment are not necessary. Fluvastatin has not been studied at doses greater than 40 mg in patients with severe renal impairment exercise caution when treating such patients at higher doses. 

A 61-year-old woman developed symptoms of acute hepatitis 6 weeks after she began to take fluvastatin sodium 20 mg/day for hypercholesterolemia (3). Ultrasonography and liver biopsy confirmed the diagnosis of non-obstructive intrahepatic jaundice. Studies of viral markers and autoimmune factors excluded viral hepatitis and autoimmune hepatitis. There was a high serum concentration of a metabolite of fluvastatin, suggesting a possible anomaly of drug metabolism. All liver function tests normalized 8 weeks after the withdrawal of fluvastatin. 

The effects of itraconazole 100 mg on the pharmacokinetics of fluvastatin 40 mg have been studied in a randomized, placebo-controlled, crossover study in 10 healthy volunteers (9). Itraconazole had no significant effect on the Cmax or total AUC of fluvastatin, but slightly prolonged its half-life. 

HMG CoA reductase inhibitors can be associated with small rises in alanine transaminase activity, but have not been definitely associated with severe morbidity involving altered hepatic function. The results of randomized trials do not suggest that statins in standard doses are hepato-toxic. In none of the large randomized studies in which standard doses were assessed (atorvastatin 10 mg/day, fluvastatin 40-80 mg/day, pravastatin 40 mg/day, simvastatin 20-40 mg/day) was there any clear excess risk of hepatitis or any other serious liver-related adverse events. Long-term large randomized trials have confirmed an excess of persistent rises in transaminases with atorvastatin 80 mg/day compared with lower doses or placebo, and similarly some excess with simvastatin 80 mg/day, but hepatitis and liver failure were not reported (4). 

In a randomized, double-blind, crossover study in 12 healthy volunteers, fluconazole increased the plasma concentrations of fluvastatin and prolonged its elimination the mechanism was probably inhibition of the CYP2C9-mediated metabolism of fluvastatin (70). Care should be taken if fluconazole or other potent inhibitors of CYP2C9 are given to patients using fluvastatin. 

Physicians should check for lipid-lowering drugs before treating elderly individuals with itraconazole (73). Susceptibility to this interaction varies from statin to statin, in that simvastatin is more affected than pravastatin (74). Concomitant use of simvastatin with itraconazole should be avoided, and the same holds true for atorvastatin (75). In another study, the blood concentration of fluvastatin was not significantly increased, whereas that of lovastatin was (76). 

The FLORIDA study recruited 540 patients with Ml and a total cholesterol level of <6,5 mmol/L and randomized them to either fluvastatin 80 mg daily or placebo at a median time of eight days after symptom onset (22). The primary composite endpoint of the study was ischemia on ambulatory electrocardiogram monitoring or a major clinical event defined as death,... 

Arampatzis CA, Goedhart D, Serruys FW, Saia R Lemos PA, de Feyter R Fluvastatin reduces the impact of diabetes on long-term outcome after coronary intervention—a Lescol Intervention Prevention Study (LIPS) substudy. Am Heart J 2005 149 329-335. 

Lee CH, de Feyter R Serruys PW, et al. Beneficial effects of fluvastatin following percutaneous coronary intervention in patients with unstable and stable angina results from the Lescol intervention prevention study (LIPS). Heart 2004 90 ... 

Ose, L. and Scott, R. for the Simvastatin-Fluvastatin Study Group (1995). Clin. Drug Invest. 10, 127—138. 

Jones PH, Kafonek S, Laurora I, et al. Comparative dose efficacy study of ator-vastatin versus simvastatin, pravastatin, lovastatin and fluvastatin in patients with hypercholesterolemia. (The CURVES study). Am.J. Cardiol., 1998, 81, 582-587. 

Lopez-Aguilar, E., Sepulveda-Vildosola, A.C., Betanzos-Cabrera, Y., Rocha-Moreno, Y.G., Gascon-Lastiri, G., Rivera-Marquez, H., Wanzke-del-Angel, V., Cerecedo-Diaz, F., and de la Cruz-Yanez, H. (2008). Phase II study of metronomic chemotherapy with thalidomide, carboplatin-vincristine-fluvastatin in the treatment of brain stem tumors in children. Arch Med Res 39 655-662. 

The effects of fluconazole on plasma fluvastatin and pravastatin concentrations have been studied in two separate, randomized, double-blind, two-phase, crossover studies... 

Recently, the HMG-CoA reductase inhibitor fluvastatin was reported to reduce urinary protein excretion in moderately proteinuric (0.6 to 1.6 g/day) patients who had IgA nephropathy with normal renal function. Creatinine clearance remained stable during the 6-month study. Longer-term evaluation in a larger patient population will be needed to confirm the effect of this class of agents. 

Studies have suggested that fluvastatin and rosuvastatin can increase warfarin levels and/or effects. Other studies with atorvas-tatin, lovastatin, pravastatin, and simvastatin suggest that they do not usually significantly alter the effects of warfarin, although cases of bleeding have been seen when these statins were given with coumarins and fluindione. 

In a crossover study in 18 patients, fluvastatin 40 mg caused no significant changes in the pharmacokinetics of digoxin 100 to 375 micrograms daily. Another similar study in patients found changes of up to 15% in maximum plasma digoxin levels and clearance, but these were not considered to be clinically relevant. ... 

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