Severe rosuvastatin accumulation with rhabdomyolysis due to drug interactions and low cardiac output syndrome

An 85‐year‐old patient presented to the emergency department because of orthopnoea and peripheral oedema. He was known for diabetes mellitus and coronary artery disease with severe chronic heart failure. Eighteen months earlier, he already showed biventricular dilatation and systolic dysfunction (20‐25% left ventricular ejection fraction) with moderate mitral valve regurgitation at transthoracic echocardiography. On current physical examination, he showed moderate oedema of the legs. On chest X‐ray, there was upper lobe pulmonary venous congestion and small bilateral pleural effusion. Laboratory testing revealed moderate creatinine elevation (150 μmol L⁻¹; normal <107). Liver enzymes and creatine kinase levels were normal. The patient's daily therapy consisted of acetylsalicylic acid 100 mg, metoprolol 50 mg, sacubitril/valsartan 200 mg (97/103 mg), torasemide 10 mg, spironolactone 12.5 mg, rosuvastatin 10 mg, and sitagliptin 100 mg.

He was admitted to the general internal medicine ward with a diagnosis of subacute biventricular decompensation, but his condition progressively deteriorated with oliguria, worsening dyspnoea, and increasing peripheral oedema despite the administration of loop diuretics. Amiodarone was introduced because of non‐sustained ventricular tachycardia at 24‐hour continuous ECG monitoring. Five days later, the patient began to feel muscular weakness and to walk unstable. After another week, he showed peripheral vasoconstriction with large pitting oedema, a slight scleral jaundice, and complained of widespread muscular pain. Laboratory tests revealed that creatinine had risen to 513 μmol L⁻¹, GPT (ALT) to 1103 U L⁻¹ (normal <51), bilirubin to 41.7 μmol L⁻¹ (normal <21.0), and lactate to 4.1 mmol L⁻¹ (normal <2.2). Moreover, creatine kinase levels were 6794 U L⁻¹ (normal <190), hs troponin T was 204 ng L⁻¹ (normal <14), and urine analysis revealed myoglobinuria. He was admitted to the intensive care unit, where severe cardiac dysfunction was confirmed by transthoracic echocardiography and trans‐pulmonary thermodilution. A diagnosis of low‐cardiac output syndrome with multi‐organ dysfunction was made. The origin of the rhabdomyolysis was thoroughly investigated: Infections (bacterial, viral, or parasitic), trauma, thermal injury, or toxins were ruled out or were deemed unlikely. Thyroid function was normal; blood sugar and electrolytes (phosphates, potassium) were within the normal range or only slightly elevated. We hypothesized that rhabdomyolysis was caused by the accumulation of the 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase‐inhibitor rosuvastatin, as statins are known to be one of the top three prescription drugs responsible for elevations of creatine kinase levels.1

Sacubitril/valsartan and rosuvastatin were discontinued, and a dobutamine infusion was initiated which led to improvement of the haemodynamic parameters, normalization of lactate levels, rapid decrease of liver enzymes, and recovery of a valid diuresis. Crystalloid and sodium bicarbonate infusions were started, aiming at volume repletion and urine alkalinisation, to limit the renal toxicity of the haem pigments. A water balance adequate to the cardiac condition was maintained by loop diuretics. Five days later, creatine kinase reached a peak value of 18478 U L⁻¹ and then began to decrease daily by 30‐50%. Creatinine stabilized at around 380 μmol L⁻¹ without the need for renal replacement treatment.

Four sequential plasma concentrations of rosuvastatin 38, 61, 72, and 85 hours after the last rosuvastatin intake were analysed by liquid chromatography/mass spectrometry (Figure 1). Concentrations measured more than 36 hours after the last dose were well above the levels usually seen in patients receiving rosuvastatin 10 mg once daily. These concentrations were even remarkably higher than those expected at peak2 and may be explained by the co‐existence of several factors: acute liver injury combined with acute renal failure, and drug‐drug interactions. Actually, rosuvastatin plasma concentrations are known to increase about 3‐fold in patients with severe renal impairment (CrCl <30 mL minute⁻¹).3 Furthermore, C_max and AUC may be increased in patients with Child‐Pugh class B hepatic impairment.4

Figure 1.

Comparison between measured rosuvastatin plasma concentrations in the index patient and mean plasma values found in 10 healthy subjects after a single oral dose of 10 mg. Adapted from J. Gao et al.2

Rosuvastatin is a substrate of OATP1B1, and interactions have been described with OATP inhibitors. Notably, the interaction with faldaprevir, an OATP‐inhibiting anti‐HCV medication, can lead to increases in AUC and Cmax of rosuvastatin of 15‐ and 33‐fold, respectively.5

Sacubitril is an OATP inhibitor, and a physiologically based pharmacokinetic model predicted a moderate interaction between sacubitril and atorvastatin, with a 1.7‐fold increase of Cmax and a 1.3‐fold increased AUC.6 In fact, one case of severe rhabdomyolysis was reported after 3 weeks of coadministration of sacubitril/valsartan and atorvastatin.7 However, atorvastatin is largely eliminated by CYP3A4, with little contribution from OATP. Since only approximately 10% of an orally administered rosuvastatin dose is metabolized,8 its elimination is much more dependent on OATP. Furthermore, rosuvastatin has a slightly higher affinity for OATP1B1 compared to atorvastatin.9 It seems therefore reasonable to assume that the magnitude of the interaction would be greater with coadministration of sacubitril and rosuvastatin. Actually, in a recent animal study, rosuvastatin AUC was increased 11‐fold by coadministration of sacubitril/valsartan to rats.10

Valsartan itself is also an OATP1B1 inhibitor, with IC50 values comparable to sacubitril.11, 12 LBQ657, sacubitril's active metabolite, is only a weak inhibitor of OATP1B1.12 However, its longer half‐life and higher plasma concentrations compared to sacubitril, especially in the presence of renal failure, potentially reinforced this interaction and resulted in a clinically significant effect.13, 14

Finally, amiodarone could have slightly contributed to increasing rosuvastatin concentrations due to the inhibition of enzymes partially responsible for the metabolism of rosuvastatin, such as CYP2C9. The Naranjo Adverse Drug Reaction Probability Scale score was 6, making it probable that the adverse drug reaction was precipitated by amiodarone, as the last factor added to those already existing.15

In conclusion, this case suggests that the interaction between rosuvastatin, sacubitril/valsartan, and amiodarone can significantly increase rosuvastatin plasma concentrations, with subsequent rhabdomyolysis, especially in patients who develop renal and liver failure due to severe heart dysfunction. Sacubitril/valsartan has already been included in the guidelines for the treatment of chronic heart failure; therefore, particular attention must be paid when treating patients who are increasingly receiving this combination of drugs.

COMPETING INTERESTS

There are no competing interests to declare.

Previsdomini M, Graziano E, Decosterd L, Courlet P, Perren A, Ceschi A. Severe rosuvastatin accumulation with rhabdomyolysis due to drug interactions and low cardiac output syndrome. Br J Clin Pharmacol. 2019;85:1616–1618. 10.1111/bcp.13950