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A screening study of drug-drug interactions in cerivastatin users: an adverse effect of clopidogrel.

ABSTRACT: An analysis of a case-control study of rhabdomyolysis was conducted to screen for previously unrecognized cytochrome P450 enzyme (CYP) 2C8 inhibitors that may cause other clinically important drug-drug interactions. Medication use in cases of rhabdomyolysis using cerivastatin (n = 72) was compared with that in controls using atorvastatin (n = 287) for the period 1998-2001. The use of clopidogrel was strongly associated with rhabdomyolysis (odds ratio (OR) 29.6; 95% confidence interval (CI), 6.1-143). In a replication effort that used the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), it was found that clopidogrel was used more commonly in patients with rhabdomyolysis receiving cerivastatin (17%) than in those receiving atorvastatin (0%, OR infinity; 95% CI = 5.2-infinity). Several medications were tested in vitro for their potential to cause drug-drug interactions. Clopidogrel, rosiglitazone, and montelukast were the most potent inhibitors of cerivastatin metabolism. Clopidogrel and its metabolites also inhibited cerivastatin metabolism in human hepatocytes. These epidemiological and in vitro findings suggest that clopidogrel may cause clinically important, dose-dependent drug-drug interactions with other medications metabolized by CYP2C8.

SUBMITTER: Floyd JS

PROVIDER: S-EPMC3830936 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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A screening study of drug-drug interactions in cerivastatin users: an adverse effect of clopidogrel.

Floyd J S JS Kaspera R R Marciante K D KD Weiss N S NS Heckbert S R SR Lumley T T Wiggins K L KL Tamraz B B Kwok P-Y PY Totah R A RA Psaty B M BM

Clinical pharmacology and therapeutics 20120314 5

An analysis of a case-control study of rhabdomyolysis was conducted to screen for previously unrecognized cytochrome P450 enzyme (CYP) 2C8 inhibitors that may cause other clinically important drug-drug interactions. Medication use in cases of rhabdomyolysis using cerivastatin (n = 72) was compared with that in controls using atorvastatin (n = 287) for the period 1998-2001. The use of clopidogrel was strongly associated with rhabdomyolysis (odds ratio (OR) 29.6; 95% confidence interval (CI), 6.1- ...[more]

PMID: 22419147

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Project description:ObjectiveTo examine the comparative safety of individual NSAIDs when given concomitantly with clopidogrel.MethodsWe conducted a retrospective cohort study using Medicaid claims from five US states during 1999-2010, supplemented with Medicare claims for dual-enrollees. The exposure of interest was the first concomitant use of clopidogrel and one of the 10 selected NSAIDs after a 1-year baseline period. The outcomes were: all-cause mortality; acute myocardial infarction (AMI)/ischemic stroke; and gastrointestinal bleeding (GIB)/intracranial hemorrhage (ICH). We calculated the hazard ratio of each NSAID for each outcome, with ibuprofen as the reference drug, using high-dimensional propensity score-adjusted proportional-hazards regression models.ResultsOf 1,060,412 clopidogrel users, 268,114 concomitant NSAID users met inclusion/exclusion criteria, contributing 48,483 person-years. We observed 2,463 deaths, 2,822 AMI/ischemic stroke outcomes, and 2,620 GIB/ICH outcomes, for unadjusted incidence rates of 50.8, 58.6, and 54.3 per 1,000 person-years, respectively. Compared with ibuprofen and controlling for potential confounders, rofecoxib (hazard ratio [HR] = 1.22; 95% confidence interval [CI]: 1.04, 1.43) and valdecoxib (HR = 0.66; 95% CI: 0.48, 0.92) showed higher and lower hazards of mortality, respectively. Indomethacin showed an increased AMI/ischemic stroke hazard (HR = 1.38; 95% CI: 1.09, 1.74). For GIB/ICH, indomethacin (HR = 2.18; 95% CI: 1.74, 2.73), diclofenac (HR = 1.65; 95% CI: 1.39, 1.97), naproxen (HR = 1.47; 95% CI: 1.28, 1.70), and rofecoxib (HR = 1.26; 95% CI: 1.08, 1.48) showed higher hazards, and valdecoxib (HR = 0.73; 95% CI: 0.55, 0.98) showed a lower hazard.ConclusionThe bleeding risks of individual NSAIDs varied more markedly than thrombotic risks when used concomitantly with clopidogrel. Moreover, bleeding risk and thrombotic risk among individual NSAIDs did not appear to be inversely related to each other in the presence of clopidogrel. Further studies are needed to elucidate underlying biological mechanisms and help clinical decision-making for a better NSAID choice in clopidogrel users.

Project description:Background and purposeThe conversion of clopidogrel to its active metabolite, R-130964, is a two-step cytochrome P450 (CYP)-dependent process. The current investigations were performed to characterize in vitro the effects of different CYP inhibitors on the biotransformation and on the antiplatelet effect of clopidogrel.Experimental approachClopidogrel biotransformation was studied using human liver microsomes (HLM) or specific CYPs and platelet aggregation using human platelets activated with ADP.Key resultsExperiments using HLM or specific CYPs (3A4, 2C19) revealed that at clopidogrel concentrations >10 microM, CYP3A4 was primarily responsible for clopidogrel biotransformation. At a clopidogrel concentration of 40 microM, ketoconazole showed the strongest inhibitory effect on clopidogrel biotransformation and clopidogrel-associated inhibition of platelet aggregation with IC(50) values of 0.03 +/- 0.07 microM and 0.55 +/- 0.06 microM respectively. Clarithromycin, another CYP3A4 inhibitor, impaired clopidogrel biotransformation and antiplatelet activity almost as effectively as ketoconazole. The CYP3A4 substrates atorvastatin and simvastatin both inhibited clopidogrel biotransformation and antiplatelet activity, less potently than ketoconazole. In contrast, pravastatin showed no inhibitory effect. As clopidogrel itself inhibited CYP2C19 at concentrations >10 microM, the CYP2C19 inhibitor lansozprazole affected clopidogrel biotransformation only at clopidogrel concentrations < or =10 microM. The carboxylate metabolite of clopidogrel was not a CYP substrate and did not affect platelet aggregation.Conclusions and implicationsAt clopidogrel concentrations >10 microM, CYP3A4 is mainly responsible for clopidogrel biotransformation, whereas CYP2C19 contributes only at clopidogrel concentrations < or =10 microM. CYP2C19 inhibition by clopidogrel at concentrations >10 microM may explain the conflicting results between in vitro and in vivo investigations regarding drug interactions with clopidogrel.

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A screening study of drug-drug interactions in cerivastatin users: an adverse effect of clopidogrel.

Publications

A screening study of drug-drug interactions in cerivastatin users: an adverse effect of clopidogrel.

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