Atorvastatin/clopidogrel/ticagrelor

Abstract

Various toxicities secondary to pharmacokinetic drug interaction and no therapeutic response: case report A 75-year-old man exhibited no therapeutic response during antiplatelet therapy with clopidogrel for in-stent thrombosis. Subsequently, he developed atorvastatin toxicity, myopathy and hepatitis following concomitant administration of ticagrelor and atorvastatin for in-stent thrombosis and coronary artery disease, respectively [routes, dosages and durations of treatments to reactions onset not stated]. The man presented to his primary care physician (PCP) after experiencing 2 weeks of progressively worsening bilateral anterior thigh pain, which caused difficulty in ambulation. One month prior to the presentation, he had been hospitalised for non-ST segment elevation myocardial infarction and in-stent thrombosis after self-discontinuation of aspirin therapy. He was discharged on clopidogrel as antiplatelet therapy; however, he was found to be non-responsive to clopidogrel on platelet function tests. Therefore, the man was switched to ticagrelor. One day prior to the hospitalisation, his PCP discovered AST and ALT elevations to over 400 U/L. Therefore, he presented to the emergency room for further workup. In the emergency room, he reported that his symptoms started after the initiation of ticagrelor. His past medical history included hypertension and coronary artery disease, which was treated with five drug eluting stents. He reported adherence to medication regimen, which comprised of ticagrelor, atorvastatin, amlodipine, aspirin, hydrochlorothiazide, metoprolol and losartan. Physical exam revealed tenderness to palpation of the thighs bilaterally. AST and ALT were elevated to 228 U/L and 158 U/L respectively, and creatine kinase was elevated to 4600 U/L. Urinalysis showed small blood with 0–4 RBCs, and troponin I was 0.07 ng/mL. Hepatitis B and C serologies were negative. Urine culture showed no growth. His signs and symptoms were consistent with hepatitis and myopathy. Both myopathy and hepatitis occurred after initiation of ticagrelor, which is a known inhibitor of CYP P4503A4. Atorvastatin is metabolised by CYP P4503A4. Thus, the initiation of ticagrelor might have increased the levels of atorvastatin (pharmacokinetic interaction) and caused a dose dependent toxicity leading to hepatitis and myopathy. After admission, atorvastatin was switched to rosuvastatin. Consequently, on the next day, his AST and ALT levels decreased to 57 U/L and 121 U/L, and his CK dropped to 715 U/L. He was subsequently discharged with improved thigh pain. He presented for outpatient follow-up and continued receiving rosuvastatin.