Rationale. In this revision to our initial application we respond to reviewers comments, update the text with recent publications, and present pilot data. Cerivastatin (Baycol), an HMG-CoA reductase inhibitor (statin), was approved and marketed in early 1998 for the treatment of dyslipidemias. Soon afterwards, suspected adverse drug reaction (SADR) reports in cerivastatin users often cited rhabdomyolysis, an uncommon condition in which the breakdown of skeletal muscle cells causes pain, weakness and, in-some cases, renal failure or death. By the time that cerivastatin was withdrawn from the market in 2001, the FDA had received 1,899 SADRs for rhabdomyolysis associated with cerivastatin compared to 1,440 for all other statins combined. In an analysis conducted by FDA scientists, the relative reporting rate (RRR) of fatal rhabdomyolysis was 40 times higher among users of cerivastatin than among users of other statins. For the outcome of all fatal and non-fatal rhabdomyolysis, the RRR was 54 times higher. About half of the rhabdomyolysis cases occurred in subjects who had taken both cerivastatin and gemfibrozil. Subsequently, pharmacokinetic studies demonstrated that gemfibrozil inhibits both major metabolic pathways for cerivastatin-not only the Cytochrome P-450 (CYP) 2C8-mediated oxidation, but also the glucuronidation by uridine diphosphate glucuronysyltransferases (UGT). We hypothesize that rhabdomyolysis cases who were taking cerivastatin but not gemfibrozil had one or both of two types of risk factors: (1) medications that are known inhibitors of these enzymes; or (2) functional genetic variants in one or more of the CYP or UGT enzymes. Study design. This project is a case-control study of factors that increased the risk of rhabdomyolysis in cerivastatin users. Cases will be cerivastatin users who had rhabdomyolysis, and statin users from two on-going epidemiologic studies will serve as two complementary control groups. """"""""For cases, identified with the assistance of attorneys, a review of medical records and telephone interview will verify the diagnosis and provide information on medication use. Subjects will also return a mouthwash buccal sample for DNA extraction. All subjects will be genotyped for known functional variants in CYP2C8, UGT1A1 and UGT1A3. In the hypothesis-testing part of this case-control study, medications known to be inhibitors of these enzymes and functional variants in their genes will be evaluated as risk factors for rhabdomyolysis in cerivastatin users. Additionally, pharmacoepidemiologic analyses of the FDA AERS data will be conducted to identify other potential new drug-drug interactions. Power to detect expected effect sizes is 80% or greater. In the discovery phase of the project, the DNA of rhabdomyolysis cases who did not take gemfibrozil will be sequenced to identify new single nucleotide polymorphisms (SNPs) in CYP2C8, UGT1 Al and UGT1 A3. The functional significance of new pharmacoepidemiologic associations will be evaluated in in vitro pharmacokinetic inhibition studies. Additionally, newly discovered SNPs in CYP2C8 will be expressed in E. coli and evaluated for their functional significance. The study of cerivastatin-associated rhabdomyolysis may advance our understanding of the pharmacoepidemiology and the pharmacogenetics of CYP2C8, UGT1A1 and UGT1A3.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL078888-03
Application #
7260386
Study Section
Special Emphasis Panel (ZRG1-HOP-Q (02))
Program Officer
Jaquish, Cashell E
Project Start
2005-09-23
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
3
Fiscal Year
2007
Total Cost
$501,301
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Sondhi, Arjun; Rice, Kenneth Martin (2018) Fast permutation tests and related methods, for association between rare variants and binary outcomes. Ann Hum Genet 82:93-101
Sharfstein, Joshua M; Psaty, Bruce M (2016) Evaluation of the Cardiovascular Risk of Naltrexone-Bupropion: A Study Interrupted. JAMA 315:984-6
Floyd, James S; Brody, Jennifer A; Tiniakou, Eleni et al. (2016) Absence of anti-HMG-CoA reductase autoantibodies in severe self-limited statin-related myopathy. Muscle Nerve 54:142-4
Psaty, Bruce M; Platt, Richard; Altman, Russ B (2015) Neurotoxicity of generic anesthesia agents in infants and children: an orphan research question in search of a sponsor. JAMA 313:1515-6
Psaty, Bruce M; Shah, Sanjiv J; Gottdiener, John (2015) Letter by Psaty et al regarding article, ""Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes"". Circulation 131:e343
Floyd, James S; Psaty, Bruce M (2014) The potential risks of expedited approval of drugs for acute bacterial infections. JAMA Intern Med 174:1436-7
Psaty, Bruce M; Weiss, Noel S (2014) 2013 ACC/AHA guideline on the treatment of blood cholesterol: a fresh interpretation of old evidence. JAMA 311:461-2
Floyd, James S; Bis, Joshua C; Brody, Jennifer A et al. (2014) GATM locus does not replicate in rhabdomyolysis study. Nature 513:E1-3
Psaty, Bruce M; Goodman, Steven N; Breckenridge, Alasdair (2013) Advances in regulatory science at the Food and Drug Administration. JAMA 309:2103-4
Psaty, Bruce M; Sitlani, Colleen (2013) The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium as a model of collaborative science. Epidemiology 24:346-8

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