Fluvastatin pharmacokinetics

FLS Tse, JM Jaffe, AJ Troendle. Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers. J Clin Pharmacol 32 630-638, 1992. 

Once-daily administration of modified-release formulation of fluvastatin 80-320 mg/day was generally safe and well tolerated in 40 patients with primary hypercholesterolemia over 13 days (7). However, fluvastatin 640 mg in this formulation was not well tolerated six of seven patients had adverse events, including diarrhea, headache, and rises in serum transaminases. In addition, the pharmacokinetics of fluvastatin were non-linear at this dose, possibly because of saturation of first-pass metabolism, causing higher than expected serum drug concentrations. 

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. 

Sabia H, Prasad P, Smith HT, Stoltz RR, Rothenberg P. Safety, tolerability, and pharmacokinetics of an extended-release formulation of fluvastatin administered once daily to patients with primary hypercholesterolemia. J Cardiovasc Pharmacol 2001 37(5) 502-11. 

Garnett WR, Venitz J, Wilkens RC, Dimenna G. Pharmacokinetic effects of fluvastatin in patients chronically receiving digoxin. Am J Med 1994 96(6A) S84-6. 

Kivisto KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol 1998 46(l) 49-53. 

Niemi M, Pasanen MK, Neuvonen PJ. SLCOIBI polymorphism and sex affect the pharmacokinetics of pravastatin but not fluvastatin. Clin Pharmacol Ther 2006 80 356-366. 

Kirchheiner J, Kudlicz D, Meisel C, et al. Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (—)-3S,5R-fluvastatin and (+)-3R,5S-fluvastatin in healthy volunteers. Clin Pharmacol Ther 2003 74(2) 186-194. 

Scripture CD, Pieper JA. Clinical pharmacokinetics of fluvastatin. Clin Pharma-cokinet 2001 40(4) 263-281. 

From an analysis of changes in ciclosporin clearance and systemic availability obtained from the medical records of 100 transplant patients, atorvastatin, fluvastatin, pravastatin, and simvastatin were found to affect ciclosporin pharmacokinetics (228). 

It has been proposed that the risk of myotoxicity increases when statins are prescribed concurrently with erythromycin (83). There are no data for any pharmacokinetic interaction with fluvastatin or pravastatin, but as in the case of simvastatin the major route of metabolism of these drugs is by CYP3A4 and there is potential for an adverse interaction. 

Healthy volunteers were given oral fluconazole (400 mg on day 1 and 200 mg on days 2-4) or placebo. On day 4, they took a single oral dose of fluvastatin 40 mg or pravastatin 40 mg. Fluconazole increased the plasma AUC and the half-life of fluvastatin by 80% but had no significant effects on the pharmacokinetics of pravastatin. The mechanism of the prolonged elimination of fluvastatin was probably inhibition of CYP2C9. Pravastatin, in contrast, appears not to be susceptible to interactions with fluconazole and other CYP2C9 inhibitors. 

It has been suggested that the pharmacokinetics of fluvastatin, including extensive biliary excretion and absence of circulating active metabolites, might be associated with a low incidence of systemic adverse effects compared with other statins. In over 1800 patients treated for an average of 61 weeks, fluvastatin was safe and tolerable (SEDA-19, 408). Pooled data from clinical trials have shown that gastrointestinal symptoms occurred in 14% of fluvastatin recipients compared with 9% taking placebo other complaints occurred... 

Neuvonen PJ, Backman JT, Niemi M (2008) Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin. Clin Pharmacokinet 47 463 74... 

Keskitalo JE, Pasanen MK, Neuvonen PJ, Niemi M (2009) Different effects of the ABCG2 c.421C>A SNP on the pharmacokinetics of fluvastatin, pravastatin and simvastatin. Pharmacogenomics 10 1617-1624... 

Smit JWA, Wijnne HJA, Schobben F, Sitsen A, de Bruin TWA, Erkelens DW. Effects of alcohol consumption on pharmacokinetics, efficacy, and safety of fluvastatin. Am J Cardiol... 

A single 1-g oral dose of tolbutamide was given to two groups of 16 healthy subjects taking fluvastatin 40 mg or simvastatin 20 mg. The pharmacokinetics of the tolbutamide were affected only to a very minor extent, and the blood glucose-lowering effects of the tolbutamide were unchanged." ... 

The small changes in the pharmacokinetics of glibenclamide caused by fluvastatin and simvastatin are not understood, but they do not appear to be elinieally signifieant. The interaction between atorvastatin or simvastatin and the thiazolidinediones is thought to involve the cytochrome P450 isoenzyme CYI TAd, although this is as yet unconfirmed. 

Atorvastatin, fluvastatin and simvastatin cause small but probably clinically unimportant increases in the serum levels of digoxin. Pravastatin and rosuvastatin appear to have no effect on digoxin pharmacokinetics. 

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. ... 

Irbesartan and telmisartan appear not to alter the pharmacokinetics of simvastatin, fluvastatin does not alter the pharmacokinetics of losartan or its active metabolite, and ohnesartan appears not to interact with pravastatin. 

Meadowcroft AM, Williamson KM, Patterson JH, Hinderliter AL, Pieper JA The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healtiiy volunteers. J Clin Pharmacol (1999) 39, 418-24. 

A randomised, double-blind study in 12 healthy subjects found that fluconazole (400 mg on day 1 followed by 200 mg daily for 3 days) increased the AUC of a single 40-mg dose of fluvastatin by 84% and increased its maximum plasma level by 44%. The pharmacokinetics of the fluconazole were unaffected. In a similar study, itraconazole 100 mg daily for 4 days did not significantly affect the pharmacokinetics of fluvastatin, apart from a small increase in its half-life. ... 

Propranolol doe not cause any clinically relevant changes to the pharmacokinetics of fluvastatin, lovastatin or pravastatin. In clinical studies, the safety and efficacy of statins were not altered by the concurrent use of beta blockers as a class. 

In a study in 24 healthy subjects the pharmacokinetics of a single 40-mg dose of fluvastatin was not affected by the concurrent use of propranolol 40 mg every 12 hours for 3 days. Similarly, the same dose of propranolol caused less than an 18% reduction in the AUC of lovastatin 20 mg and its metabolites, and modestly reduced the AUC of pravastatin 20 mg and its metabolites by 16 to 23%. These changes are small and unlikely to be clinically relevant. 

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