Published: June 2012
Publications
Statins, Ciclosporin and the Risk of Myopathy
Prescriber Update 33(2): 16-17
June 2012
Patients taking a statin with ciclosporin may be at increased risk of statin-related adverse events. In patients currently taking ciclosporin, who also required lipid-lowering therapy, statins should be used with care. Prescribers should use the lowest possible dose and monitor for adverse reactions and the effectiveness of treatment.
Dyslipidaemia is common in patients who have undergone solid organ transplantation. Dyslipidaemia is estimated to occur in up to 80% of renal, pancreas, and heart transplant recipients and up to 45% of liver transplant patients. In addition, immunosuppressant therapy, including corticosteroids and ciclosporin, have all been associated with dyslipidaemia1,2. For these reasons, it is common for transplant patients to require statin therapy. PHARMAC data indicates that approximately one third of patients taking ciclosporin are also taking a statin.
Pharmacokinetic studies confirm that ciclosporin interacts with all statins to increase the plasma levels of the statin3,4. Ciclosporin is an inhibitor of CYP3A4 as well as several membrane transporters, including OATP2 and P-glycoprotein5. The metabolic pathways of statins include CYP3A4, OATP2 and P-glycoprotein (Table 1). It has been suggested that the risk of myopathy is lower with non-lipophilic statins because of their inability to enter muscle cells and to alter membrane structure6.
Table 1: Characteristics of statins available in New Zealand2
| Statin | Equipotent doses (mg/day) | CYPmetabolism | P-glycoprotein substrate | OATP2 substrate | Lipophilic |
|---|---|---|---|---|---|
| Atorvastatin | 5 | 3A4 | Yes | Yes | Yes |
| Pravastatin | 20 | None | Yes | Yes | No |
| Rosuvastatin | ? | 2C9 (minor) | No | Yes | No |
| Simvastatin | 10 | 3A4 | Yes | Possibly | Yes |
*Equivalent dose to reduce LDL-cholesterol from baseline by 25–30%.
Myopathies are the most severe adverse reaction to statin therapy. The risk of myopathy increases with increasing plasma levels of statins7. Clinical studies have estimated the following incidence of myopathies in patients taking statins6.
- Myopathy – 5 patients per 100,000 person years
- Rhabdomyolysis – 1.6 patients per 100,000 person-years
- Myalgia or myositis – 2–7% of patients
- Elevated creatine kinase – 11–63% of asymptomatic patients.
Other risk factors for statin-induced myopathy include female gender, a decline in renal or hepatic function, low body mass index, hypothyroidism and a personal or family history of symptoms associated with rhabdomyolysis.
In New Zealand, PHARMAC fully subsidises simvastatin, atorvastatin and pravastatin. Rosuvastatin has consent for distribution in New Zealand but is not currently subsidised.
References
- Martin JE, Cavanaugh TM, Trumbull L, et al. 2008. Incidence of adverse events with HMG-CoA reductase inhibitors in liver transplant patients. Clinical Transplantation 22: 113-9.
- Kahwaji JM, Dudek RR. 2006. How can we manage hyperlipidemia and avoid rhabdomyolysis in transplant patients? Permanente Journal 10: 26-8.
- Shitara Y, Sugiyama Y. 2006. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacology and Therapeutics 112: 71-105.
- Kalliokoski A, Niemi M. 2009. Impact of OATP transporters on pharmacokinetics. British Journal of Pharmacology 158: 693-705.
- Neuvonen PJ, Backman JT, Niemi M. 2008. Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin. Clinical Pharmacokinetics 47: 463-74.
- Tomaszewski M, Stepien KM, Tomaszewska J, et al. 2011. Statin-induced myopathies. Pharmacological Reports 63: 859-66.
- Arrow Pharmaceuticals (NZ) Limited. 2011. Arrow Simva Data Sheet 7 September 2011. URL: www.medsafe.govt.nz/profs/Datasheet/a/ArrowSimvatab.pdf (Adobe PDF document 161KB) (accessed 25 May 2012).
