Rosuvastatin‐Induced Rhabdomyolysis – Possible Role of Ticagrelor and Patients’ Pharmacogenetic Profile

• Published in: Basic & clinical pharmacology & toxicology 2018-10, Vol.123 (4), p.509-518
• Main Authors: Vrkić Kirhmajer, Majda, Macolić Šarinić, Viola, Šimičević, Livija, Ladić, Iva, Putarek, Krešimir, Banfić, Ljiljana, Božina, Nada
• Format: Article
• Language: English
• Subjects: Age Factors; Aged; Aged, 80 and over; Amiodarone; CYP2D6 protein; Cytochrome P450; Drug Interactions; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics; Kidney - physiopathology; Male; Middle Aged; Patients; Pharmacogenetics; Pharmacogenomic Testing; Pharmacogenomic Variants; Pharmacology; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - adverse effects; Platelet Aggregation Inhibitors - pharmacokinetics; Polypharmacy; Predictive Value of Tests; Proton pump inhibitors; Renal Insufficiency, Chronic - complications; Renal Insufficiency, Chronic - physiopathology; Rhabdomyolysis; Rhabdomyolysis - chemically induced; Rhabdomyolysis - diagnosis; Rhabdomyolysis - physiopathology; Risk Factors; Rosuvastatin Calcium - administration & dosage; Rosuvastatin Calcium - adverse effects; Rosuvastatin Calcium - pharmacokinetics; Statins; Ticagrelor - administration & dosage; Ticagrelor - adverse effects; Ticagrelor - pharmacokinetics
• ISSN: 1742-7835; 1742-7843
• DOI: 10.1111/bcpt.13035

Up to the beginning of 2018, a total of eight cases describing rare but clinically important drug interactions between rosuvastatin and ticagrelor which resulted in rhabdomyolysis have been noted in the Global World Health Organization (WHO) adverse drug reaction (ADR) database (VigiBase) as well as in available literature. There are several possible factors which could contribute to the onset of rhabdomyolysis: old age, initially excessive rosuvastatin dose, drug–drug interactions (DDI) on metabolic enzymes (CYPs and UGTs) and drug transporter levels (ABCB1, ABCG2, OATP1B1) and pharmacogenetic predisposition. We reviewed all available cases plus the case of an 87‐year‐old female Croatian/Caucasian patient who developed rhabdomyolysis following concomitant treatment with rosuvastatin and ticagrelor. The results of the pharmacogenetic analysis indicated that the patient was a carrier of inactivating alleles CYP2C9*1/*3, CYP3A4*1/*22, CYP3A5*3/*3, CYP2D6*1/*4, UGT1A1*28/*28, UGT2B7 ‐161C/T, ABCB1 3435C/T and ABCB1 1237C/T which could have added to the interactions not only between ticagrelor and rosuvastatin but also other concomitantly prescribed medicines, such as amiodarone and proton pump inhibitors. In this case report, the possible multifactorial causes for rhabdomyolysis following concomitant use of rosuvastatin and ticagrelor such as old age, polypharmacy, renal impairment, along with pharmacogenetics will be discussed.