Ignite Creation Date:
2024-05-05 @ 12:06 PM
Last Modification Date:
2024-10-26 @ 9:20 AM
Study NCT ID:
NCT00241748
Status:
COMPLETED
Last Update Posted:
2012-01-05
First Post:
2005-10-17
Brief Title:
Pharmacoepidemiology and Pharmacogenetics of a Statin Adverse Event
Sponsor:
University of Washington
Organization:
University of Washington
Study Overview
Official Title:
Pharmacoepidemiology and Pharmacogenetics of a Statin Adverse Event
Status:
COMPLETED
Status Verified Date:
2012-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
To conduct a case-control study of factors that increased the risk of rhabdomyolysis an adverse drug reaction in cerivastatin users
Detailed Description:
BACKGROUND
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skeletal muscle cells causes pain weakness and in-some cases renal failure or death By the time that cerivastatin was withdrawn from the market in 2001 the FDA had received 1899 SADRs for rhabdomyolysis associated with cerivastatin compared to 1440 for all other statins combined In an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 The investigators 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
Coronary heart disease CHD is the leading cause of morbidity and mortality in the US and statin agents are commonly employed for the treatment of hyperlipidemia one of the principal risk factors for CHD Given the hundreds of thousands to millions of Americans presently on statin therapy and the potentially serious though relatively rare complication of rhabdomyolysis this is a significant topic to study
DESIGN NARRATIVE
The investigators 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 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
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 1899 SADRs for rhabdomyolysis associated with cerivastatin compared to 1440 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 The investigators 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
Coronary heart disease CHD is the leading cause of morbidity and mortality in the US and statin agents are commonly employed for the treatment of hyperlipidemia one of the principal risk factors for CHD Given the hundreds of thousands to millions of Americans presently on statin therapy and the potentially serious though relatively rare complication of rhabdomyolysis this is a significant topic to study
DESIGN NARRATIVE
The investigators 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 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| R01HL078888 | NIH | None | httpsreporternihgovquickSearchR01HL078888 |