Simvastatin is among the most commonly used prescription medications for cholesterol reduction and the most common statin-related adverse drug reaction is skeletal muscle toxicity. Multiple factors have been shown to influence simvastatin-induced myopathy. In addition to age, gender, ethnicity, genetic predisposition, and dose, drug-drug interactions play a major role. This is particularly true for drugs that are extensively metabolized by cytochrome P450 (CYP)3A4. We describe a particularly severe case of rhabdomyolysis after the introduction of ciprofloxacin, a weak CYP3A4 inhibitor, in a patient who previously tolerated the simvastatin-amlodipine combination.
Extremely severe rhabdomyolysis with statin therapy remains rare, in comparison with myalgias or mild elevation of muscular enzymes. Among precipitating factors, drug-drug interactions are playing an important role and should be investigated in depth. We are reporting a case of impressive rhabdomyolysis occurring soon after the introduction of antimicrobial therapy in patient who acquired peritoneal dialysis-related peritonitis.
A 41-year-old African woman presented to the hospital for diffuse myalgia and intense weakness developing over the last 3 days. Her previous medical history included systemic lupus erythematosus (SLE) complicated by severe glomerulonephritis. After progression of renal failure, she required peritoneal dialysis (PD) for the last 3 years. She was on automated PD with 3 exchanges of 1,800 mL during the night and fill volume of 1,500 mL with icodextrin during daytime. Current medications included furosemide 125 mg b.i.d., amlodipine 10 mg o.d., bisoprolol 10 mg o.d., irbesartan 300 mg o.d., mycophenolate mofetil 500 mg o.d., hydroxychloroquine 200 mg b.i.d., calcium carbonate 1 g b.i.d., colecalciferol 625
She was admitted to the intensive care unit (ICU) for the correction of electrolyte disorders and fluid balance. Serum CK peaked at 816,000 IU/L on day 2 and then progressively decreased. Peritoneal dialysis therapy was maintained (3 exchanges/day) and PDE progressively cleared. Peritonitis also progressively resolved. Renal function recovered partially with spontaneous reapparition of dark tea-colored urine output (600 mL/d). A right vastus lateralis needle muscle biopsy was performed. The biopsy was of small size and was normal except for increased size and amount of lipid droplets. Serum carnitine and acylcarnitine levels were normal. Lymphocyte carnitine palmitoyl-CoA transferase 2 activity was increased.
Genetic analysis was performed to identify potential gene variants responsible for altered absorption, distribution, metabolism, and excretion of statins and/or for higher susceptibility to myopathy. The patient was cytochrome P-450 (CYP) 3A4
This patient developed a severe rhabdomyolysis soon after the introduction of an antimicrobial therapy for a PDRP. The pathogen that was identified, namely,
Among the main etiologies of rhabdomyolysis (traumatism, exertion, muscle hypoxia, genetic defects, infection, hypo- or hyperthermia, and metabolic and electrolyte disorders), drugs and toxins are playing a significant role [
Statins are widely prescribed in developed countries. Although generally safe, they can induce muscle disorders ranging from myalgias without any biologic abnormality to life-threatening rhabdomyolysis. Statin-related rhabdomyolysis (SRR), usually defined as CK levels exceeding 10 times the upper limit of normal range, is reported to be very infrequent (in comparison with myopathy or myalgias), with an incidence of 0.01% for five-year therapy [
Statins metabolism varies from one type to another. After passive absorption by the intestinal cells, simvastatin is transported from the portal blood to the hepatocytes by an influx pump, the organic anion-transporting polypeptide 1B1 (OATP1B1). Simvastatin is an inactive lactone that is then predominantly (≥80%) metabolized by CYP3A4 and 3A5 with a little contribution of CYP2A8 (≤20%) into
While an interaction between statins and other drugs on the CYP3A4 metabolic pathway is well known, the implication of other mechanisms has been suggested. Among these, glycoprotein P (P-gp) inhibition could play a role. P-gp is an active tissue-specific drug transporter belonging to the ATP-binding cassette superfamily. Acting as an efflux pump, it avoids cellular uptake of several drugs and toxins, preventing notably their absorption through the gastrointestinal tract. As simvastatin is not only an inhibitor but also a substrate of the P-gp, inhibition of P-gp by other drugs may increase serum levels of simvastatin when coadministered [
The multiple drug protein 2 (MRP2) is another membrane transport protein from the ABC superfamily excreting toxins into bile that could play a role in drug-drug interactions as simvastatin is also a substrate of this transporter [
Several genetic factors may predispose to statin-related toxicity [
To date, only two other cases of rhabdomyolysis after drug interaction between simvastatin and ciprofloxacin have been reported, but none with a simvastatin-amlodipine interaction [
Several other risk factors for SRR could also have influenced the severity of the rhabdomyolysis in our patient. First, CK levels are known to be higher in black people [
In conclusion, this case illustrates the potentially dangerous interactions of some statins (simvastatin) with drugs that are also metabolized by the CYP3A4/5 pathway, even in the absence of genetic predisposing factors. While the US Food and Drug Administration (FDA) has advised that the daily dose of simvastatin should not exceed 20 mg in patients taking amlodipine concomitantly, the introduction of a new drug, even considered as a weak CYP3A4 inhibitor like ciprofloxacin, could increase the risk of myotoxicity [
A written authorization was obtained from the patient for the publication.
The authors declare that there is no conflict of interests regarding the publication of this paper.