Double trouble: ciclosporin–simvastatin coinduced rhabdomyolysis

Abstract

A 73-year-old woman presented with an acute exacerbation of her long-standing psoriasis. Ciclosporin was commenced due to the severity of her symptoms resulting in remission within 2 weeks. Full blood count, urea and electrolytes following initiation of treatment were unremarkable, although she complained of muscle aches, which was attributed to her known multiple sclerosis. Three weeks later she was admitted to the hospital with diarrhoea and vomiting. Repeat blood tests revealed raised creatinine (528 μmol/L (normal range (NR) n=45–84 μmol/L)), urea (32.6 mmol/L (NR 2.5–7.8 mmol/L)) and creatine kinase (6792 IU/L (NR 25–200 IU/L)) levels and reduced estimated glomerular filtration rate of 7. A diagnosis of acute kidney injury secondary to rhabdomyolysis was made due to an interaction between ciclosporin and simvastatin, precipitated by the dehydration from gastroenteritis. Haemofiltration was required to stabilise her renal function and she made a complete recovery.

Background

Drug interactions result in a significant number of hospital admissions. Statins (hydroxymethylglutaryl-CoA reductase inhibitors) are widely used as lipid-lowering agents in the primary and secondary prevention of cardiovascular disease. Ciclosporin is an immunosuppressant that acts on T-cells by inhibiting calcineurin phosphorylase. It is used in the treatment of inflammatory dermatoses and as an anti-rejection therapy after organ transplants. As a large number of patients are on these treatments, it is important for physicians to be aware of the potential interaction between ciclosporin and statins.

Case presentation

A 73-year-old woman presented to the dermatology department with an exacerbation of her long-standing psoriasis. Extensive plaques with pustular margins affecting her trunk, lower abdomen and proximal limbs were evident. Psoriasis Area and Severity Index (PASI) was 21.4. She had previously been managed with acitretin and achieved good remission, but had not required any treatment for almost 6 years. Her past medical history included multiple sclerosis, chronic obstructive pulmonary disease and gastritis. Her medical history was negative for liver disease. Surgical history included a cholecystectomy secondary to gallstone disease, complicated by pancreatitis and a double mastectomy for breast carcinoma. Medications at presentation included amiloride-furosemide, gabapentin, omeprazole, simvastatin and zopiclone. Treatment options considered included ciclosporin (for a rapid response due to pustular lesions that indicated unstable, active psoriasis) or acitretin (which had previously conferred good benefit). The patient preferred a trial of ciclosporin due to her considerable symptoms. This resulted in excellent remission within 2 weeks. Her only symptom was muscle aches, which were attributed to her long-standing multiple sclerosis. However, 3 weeks later she was admitted to hospital following a brief history of diarrhoea, vomiting and reduced urine output.

Investigations

Before commencing ciclosporin, baseline blood investigations including full blood count, renal and liver function were unremarkable. Repeat bloods during her hospital admission revealed a creatinine of 528 μmol/L (normal range (NR) 45–84 μmol/ L), urea of 32.6 mmol/L (NR 2.5–7.8 mmol/L), potassium of 7 mmol/L (NR 3.5–5.0 mmol/L) and estimated glomerular filtration rate of 7. Her creatine kinase (CK) level was elevated at 6792 IU/L (NR 25–200 IU/L), supporting the diagnosis of acute kidney injury secondary to rhabdomyolysis. This was attributed to the interaction between ciclosporin and simvastatin, precipitated by dehydration secondary to gastroenteritis. Myoglobinuria was not measured at the time because of the classical features of rhabdomyolysis. However, the urine was noted to be dark in colour. CK peaked on day 2 of admission (7265 IU/L) and declined back to normal levels within 6 days, further supporting the diagnosis of acute rhabdomyolysis.

Differential diagnosis

Although the case demonstrates a typical clinical picture of rhabdomyolysis, similar findings could be accounted for by an inflammatory myopathy, immune-mediated necrotising myopathy or a silent myocardial infarction. An inflammatory aetiology for the myopathy was unlikely at presentation as C-reactive protein was only mildly elevated at 25 mg/L (NR 0–5 mg/L), myositis antibody profile was negative and magnetic resonance imaging showed no evidence of a proximal myositis. There was no clinical or biochemical suggestion of any cardiac pathology.

Treatment

On admission, the patient’s elevated potassium was treated with insulin and dextrose. Haemofiltration was later required to normalise her declining renal function. Ciclosporin and the simvastatin were promptly stopped.

Outcome and follow-up

The patient recovered fully. Following normalisation of renal function, simvastatin was restarted. Ciclosporin was indefinitely stopped. Acitretin is currently being used to treat her psoriasis which is well controlled. We have now adapted our policy and avoided co-prescribing ciclosporin and statins. This recommendation has recently been included in the ‘British Association of Dermatologists guidelines for the safe and effective prescription of oral ciclosporin in dermatology’.¹

Discussion

Ciclosporin is a frequently prescribed immunosuppressant which works by inhibiting the transcription of cytokines involved in T-cell activation.² It has a variety of adverse effects including nephrotoxicity, causing electrolyte disturbances such as hyperkalaemia and hypomagnesaemia. Hypertension, gingival hyperplasia and hyperlipidaemia have also been reported.³ Careful monitoring is required for any patient taking ciclosporin due to its narrow therapeutic range. It is a substrate for CYP3A, a common pathway for the metabolism of many drugs. Therefore, there are important potential drug interactions with various medications including statins, calcium channel blockers and macrolide antibiotics.⁴

Statins such as atorvastatin, pravastatin and simvastatin are lipid-lowering agents, which act by inhibiting 3-hydroxy-3-methylgutaryl coenzyme-A reductase. They comprise a large group of drugs with significant pharmacokinetic variability that heightens their potential for drug-drug interactions. Atorvastatin, lovastatin and simvastatin are substrates metabolised by the cytochrome CYP450 system, in particular the CYP3A4 pathway. Pravastatin is only partly metabolised by CYP3A4. Its major metabolite, 3-α-iso pravastatin, is formed by acid degradation in the stomach and, unlike other statins, it is predominantly excreted by the kidneys.⁵ This flexible elimination process is significant as it potentially explains why pravastatin has a reduced risk of drug interactions compared with other statins.

Concomitant use of these statins with ciclosporin can result in elevated plasma concentrations of statins. A number of adverse events, such as rhabdomyolysis, have been observed over the years in ciclosporin-treated patients.⁶ The first case of this interaction was reported in a cardiac transplant patient receiving ciclosporin and gemfibrozil.⁷ Both these immunosuppressive drugs were found to significantly increase the risk of statin-induced myopathy. Multiple pharmacokinetic studies have subsequently investigated the interaction; however, this has largely been in cardiac or renal transplant patients and not in psoriasis patients. Arnadottir et al showed a threefold higher systemic exposure of simvastatin in five ciclosporin-treated renal transplant patients compared with five non-transplanted patients.⁸ The main proposed mechanisms for this effect are the competitive inhibition of CYP3A4 and the efflux pump, P-glycoprotein. The precise mechanisms remain unknown. Fluvastatin is mainly metabolised by CYP2C9 and is less likely to interact with ciclosporin, which highlights the important role of the CYP3A4 pathway in this interaction. However, regardless whether CYP3A4 is the primary metabolic pathway, there is still increased systemic exposure of all statins when coadministered with ciclosporin. Therefore, the inhibition of the CYP3A4 pathway cannot be the sole mechanism of the interaction. Another possible mechanism is the inhibition of statin transport in the liver. Organic anion-transporting polypeptides (OATPs) are a family of membrane transporters that are crucial for pharmacokinetics.⁹ OATP1B1 is expressed on the sinusoidal membranes of hepatocytes, thus mediating the hepatic uptake of drugs, such as statins.¹⁰ Ciclosporin has been found to inhibit the OATP1B1 transporter, which demonstrates another mechanism for the interaction between ciclosporin and statins. Moreover, there is marked genetic polymorphism of the OATP1B1 transporters, which helps explain interindividual variability in drug pharmacokinetics.¹¹ A single nucleotide variant (c.521T>C, p.Val174Ala) in the SCLO1B1 gene decreases the ability of OATP1B1 to transport simvastatin, resulting in an enhanced risk of statin-induced myopathy.⁹ Although not the focus of our case report, these advances in pharmacogenomics help us understand variability in drug response within populations.

As ciclosporin and most statins are metabolised by the CYP3A4, statins theoretically also have the potential to increase systemic exposure of ciclosporin. However, the literature suggests that this does not occur. In fact, Asberg et al showed that there was a minimal (but not clinically significant) reduction of ciclosporin levels when coadministered with statins.¹²

Other commonly prescribed drugs can also affect the CYP3A pathway. Strong inhibitors such as itraconazole and ritonavir, and mild inhibitors such as grapefruit juice and verapamil can further increase serum concentrations of simvastatin and lovastatin. Physicians should ensure that simvastatin and lovastatin are not prescribed with strong inhibitors of the CYP3A pathway to reduce the risk of myotoxicity. Close medical supervision is required when mild inhibitors are prescribed concurrently with simvastatin and lovastatin.

Rhabdomyolysis is a clinical diagnosis comprising muscle symptoms associated with significantly elevated CK and creatine levels.¹³ It is often associated with vigorous exercise. Health-related and demographic factors can predispose an individual to developing statin-induced rhabdomyolysis.¹⁴ Some of these factors were present in our patient, including older age, dehydration from gastroenteritis, multisystem diseases and polypharmacy. A number of cases of rhabdomyolysis have occurred in patients concurrently taking ciclosporin and either simvastatin or lovastatin. Fluvastatin and pravastatin are less subject to this interaction and it may be prudent to choose one of these in patients already treated with ciclosporin.

Learning points.

• Physicians should be aware of rhabdomyolysis as a side effect in patients taking both a statin and ciclosporin. Simvastatin and lovastatin should be avoided in patients taking ciclosporin.

• If necessary, pravastatin should be the primary statin used in patient’s concurrently taking ciclosporin due to fewer interactions.

• A variety of drugs also affect the CYP3A pathway. Care must be taken to avoid prescribing other inhibitors concurrently with ciclosporin and statins.