Rhabdomyolysis due to simvastatin in a transplant patient: are some statins safer than others?

Catherine M. Stirling and Christopher G. Isles

Renal Unit, Dumfries and Galloway, Royal Infirmary, Dumfries, UK

Sir,

Rhabdomyolysis is the most important side effect of statin therapy. In transplant patients it is often caused by an interaction with drugs that inhibit the cytochrome P450 isoenzyme CYP3A4, resulting in elevated serum levels of the statin. However, not all statins are metabolized by this enzyme and they therefore have different drug interaction and safety profiles. We describe a case in which failure to appreciate the possibility of a drug interaction between cyclosporin, simvastatin and clarithromycin led to rhabdomyolysis, and discuss whether some statins might be more likely to provoke rhabdomyolysis than others.

Case.

A 62-year-old woman with chronic glomerulonephritis started dialysis in 1994. During the same year, she underwent coronary artery bypass grafting and was prescribed simvastatin for hypercholesterolaemia. She received a cadaveric renal transplant in 1998 but her graft did not function well and her creatinine was 250 µmol/l on discharge. Drug treatment thereafter included prednisolone, azathioprine, cyclosporin and simvastatin 20 mg per day. Renal function remained stable during follow up with cyclosporin levels in the range of 60–80 nmol/l. In January 1999, she developed a respiratory tract infection with atypical features and was started on clarithromycin 250 mg twice daily for 10 days. At the end of treatment, her serum cyclosporin level had risen to 240 nmol/l and serum creatinine to 330 µmol/l. This was followed 10 days later by profound muscle weakness and a rise in serum creatine kinase to 7500 IU/l. There was no further deterioration in renal function and the patient's symptoms resolved with return of muscle enzymes to normal shortly after stopping simvastatin.

Discussion.

Rhabdomyolysis is an important but uncommon side effect of statins. Only one case was recorded in the 4S trial and none in WOSCOPS, AFCAPS, LIPID and CARE. With hindsight, the rhabdomyolysis in our patient was a consequence of the co-prescription of three drugs metabolized by the cytochrome P450 enzyme system.

Statins have different pharmacokinetic properties. Simvastatin, lovastatin, atorvastatin and cerivastatin are all metabolized by CYP3A4 enzyme and have the potential to interact with CYP3A4 substrates and inhibitors [1]. Co-administration of cyclosporin and clarithromycin, which are CYP3A4 inhibitors, increases statin levels and therefore increases the risk of muscle toxicity (Figure 1Go). Cerivastatin has a dual metabolism with CYP3A4 and CYP2C8 isoenzymes, but elevated serum statin concentrations can still occur in patients co-prescribed itraconazole, erythromycin and cyclosporin [2]. Fluvastatin is presumed to be a CYP2C9 substrate and has an interaction with diclofenac which is metabolized by the same enzyme [3]. Its metabolism has not been fully elucidated but no clinically significant interactions with drugs that are CYP3A4 substrates or inhibitors have been reported. Pravastatin may be metabolized to a small extent by CYP3A4, but the majority of the drug is excreted unchanged [3]. Like fluvastatin, there have been no cases of muscle toxicity caused by cytochrome enzyme mediated drug interactions.



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Fig. 1. Mechanism of drug interactions.

 
Most reported cases of rhabdmyolysis have occurred in transplant patients taking cyclosporin with either lovastatin or simvastatin [3] and most authorities now recommend that the dose of simvastatin should not exceed 10 mg, if prescribed in conjunction with cyclosporin. Pravastatin and fluvastatin do not have the same interaction with cyclosporin macrolides and other drugs and are therefore the least likely of the statins to cause muscle toxicity [4]. Pravastatin may in addition reduce the incidence of coronary vasculopathy in transplant patients [5]. We recommend that pravastatin or fluvastatin should be the statins of choice for transplant patients who require lipid-lowering therapy.

References

  1. Bays H, Dujovne CA. Drug interactions of lipid altering drugs. Drug Safety1998; 19: 355–371[ISI][Medline]
  2. Muck W, Mai I, Fritsche L et al. Increase in Cerivastatin systemic exposure after single and multiple dosing in cyclosporin treated kidney transplant patients. Clin Pharmacol Ther1999; 65: 251–261[ISI][Medline]
  3. Christians U, Jacobsen W, Floren LC. Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl/Coenzyme A reductase inhibitors in transplant patients: are the statins mechanistically similar? Pharmacol Ther1998; 80: 1–34[ISI][Medline]
  4. Twomey P. Practical statin prescribing. Prescribers' J2000; 40: 183
  5. Kobashigawa JA, Katznelson S, Laks H et al. Effect of pravastatin on outcomes after cardiac transplantation. NEJM1995; 333: 621–627[Abstract/Free Full Text]