| Title: |
Role of Drug-Gene Interactions and Pharmacogenetics in Simvastatin-Associated Pulmonary Toxicity. |
| Authors: |
Jessurun, Naomi T., Drent, Marjolein, Wijnen, Petal A., Harmsze, Ankie M., van Puijenbroek, Eugène P., Bekers, Otto, Bast, Aalt |
| Source: |
Drug Safety; Nov2021, Vol. 44 Issue 11, p1179-1191, 13p |
| Subject Terms: |
SIMVASTATIN, PULMONARY toxicology, PHARMACOGENOMICS, BIOCHEMICAL genetics, GENETIC engineering, PROTEINS, RESEARCH, ANTILIPEMIC agents, RESEARCH methodology, EVALUATION research, COMPARATIVE studies, DRUG interactions, OXIDOREDUCTASES, HEMOPROTEINS |
| Abstract: |
Introduction: 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.Objective: 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.Methods: 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.Results: 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.Conclusion: 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. CLINICALTRIALS.Gov Identifier: NCT00267800, registered in 2005. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
