Role of Drug–Gene Interactions and Pharmacogenetics in Simvastatin-Associated Pulmonary Toxicity

Abstract

Simvastatin has previously been associated with drug-induced interstitial lung disease. In this retrospective observational study, cases with non-specific interstitial pneumonia (NSIP) or idiopathic pulmonary fibrosis (IPF) with simvastatin-associated pulmonary toxicity (n = 34) were evaluated. To identify whether variations in genes encoding cytochrome P450 (CYP) enzymes or in the SLCO1B1 gene (Solute Carrier Organic anion transporting polypeptide 1B1 gene, encoding the organic anion transporting polypeptide 1B1 [OATP1B1] drug transporter enzyme), and/or characteristics of concomitantly used drugs, predispose patients to simvastatin-associated pulmonary toxicity. Characteristics of concomitantly used drugs and/or variations in the CYP or SLCO1B1 genes and drug–gene interactions were assessed. The outcome after withdrawal of simvastatin and/or switch to another statin was assessed after 6 months. Multiple drug use involving either substrates and/or inhibitors of CYP3A4 and/or three or more drugs with the potential to cause acidosis explained the simvastatin-associated toxicity in 70.5% (n = 24) of cases. Cases did not differ significantly from controls regarding CYP3A4, CYP2C9, or OATP1B1 phenotypes, and genetic variation explained only 20.6% (n = 7) of cases. Withdrawal of simvastatin without switching to another statin or with a switch to a hydrophilic statin led to improvement or stabilization in all NSIP cases, whereas all cases who were switched to the lipophilic atorvastatin progressed. Simvastatin-associated pulmonary toxicity is multifactorial. For patients with this drug-induced pulmonary toxicity who need to continue taking a statin, switching to a hydrophilic statin should be considered. NCT00267800, registered in 2005.