M. K. Itkonen, A. Tornio, P. J. Neuvonen, M. Niemi, J. T. Backman; University of Helsinki, Helsinki, Finland

BACKGROUND: Simvastatin and clopidogrel are a commonly used combination in the treatment of cardiovascular diseases. Recent studies have shown that clopidogrel and its metabolites inhibit OATP1B1 and CYP2C8, which are involved in the hepatic uptake and metabolism of simvastatin, respectively.
METHODS: We studied the effect of clopidogrel on the pharmacokinetics of simvastatin in a randomized placebo-controlled crossover study with 1 week washout period in 12 healthy volunteers. In the active drug phase the volunteers received orally 300 mg of clopidogrel on day 1 and 75 mg on days 2 and 3. A 40 mg oral dose of simvastatin was administered 1 hour after ingestion of clopidogrel on days 1 and 3. In the placebo phase, 40 mg of simvastatin was ingested 1 hour after the placebo. Plasma concentrations of simvastatin, clopidogrel and their metabolites were measured up to 12 hours after simvastatin dosing in all the study phases.
RESULTS: Neither 300 mg nor 75 mg dose of clopidogrel caused a statistically significant change in plasma concentrations of simvastatin lactone or simvastatin acid, compared to placebo. With the 300 mg dose of clopidogrel, a modest 1.28-fold increase was seen in the area under the concentration-time curve (AUC0-inf) of simvastatin lactone, but it was statistically insignificant (p=0.081, 90% CI of the geometric mean ratio 0.91-1.80). After the 300 mg clopidogrel dose, the AUC0-inf of simvastatin acid was 1.10-fold of that during the placebo phase (p=0.832, 90% CI 0.72-1.68).
CONCLUSION: Since the AUC0-inf of simvastatin acid is sensitive to changes in OATP1B1 activity, and no significant change was observed in the pharmacokinetics of simvastatin lactone or simvastatin acid, it seems that clopidogrel is not a clinically relevant inhibitor of OATP1B1.