Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel

Abstract

Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC of dasabuvir 4.7-fold; range 2.0-10.1-fold (P = 8·10 ), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC 3.9-fold; range 2.1-7.9-fold (P = 2·10 ), compared with ritonavir alone. Ritonavir decreased the AUC of clopidogrel active metabolite by 51% (P = 0.0001), and average platelet inhibition from 51% without ritonavir to 31% with ritonavir (P = 0.0007). In conclusion, clopidogrel markedly elevates dasabuvir concentrations, and patients receiving ritonavir are at risk for diminished clopidogrel response.

Clopidogrel and Gemfibrozil Strongly Inhibit the CYP2C8-Dependent Formation of 3-Hydroxydesloratadine and Increase Desloratadine Exposure In Humans

“…The variation in the pharmacokinetic variables of gemfibrozil and its 1-O-glucuronide metabolite was smaller, only up to 2-fold. Consistent with previous DDI studies between clopidogrel or gemfibrozil and CYP2C8 substrates (Backman et al, 2002;Jaakkola et al, 2005;Tornio et al, 2014;Itkonen et al, 2016Itkonen et al, , 2018Itkonen et al, , 2019, no significant correlations were observed between the plasma concentrations of clopidogrel acyl-b-D-glucuronide or gemfibrozil 1-Oglucuronide and changes in desloratadine pharmacokinetics.…”

“…The resulting reduction in 3-hydroxydesloratadine:desloratadine AUC 0-71 h ratio by clopidogrel is consistent with an average 80% inhibition of CYP2C8 activity, assuming that clopidogrel had no effect on non-CYP2C8-mediated metabolism of desloratadine N-glucuronide nor on hydrolysis of either of the N-glucuronide intermediates. With respect to clopidogrel's CYP2C8 inhibition potency, this estimate is in accordance with recent findings that clopidogrel causes about 5-fold increases in exposures to repaglinide and dasabuvir, which are among the most sensitive CYP2C8 substrates identified so far (Tornio et al, 2014;Itkonen et al, 2019).…”

“…The acyl-b-D-glucuronide metabolite of the antiplatelet agent clopidogrel and the 1-O-glucuronide metabolite of the fibric acid derivative gemfibrozil act as mechanism-based inhibitors of CYP2C8 (Ogilvie et al, 2006;Tornio et al, 2014;Backman et al, 2016). Accordingly, in humans, clopidogrel and gemfibrozil have significantly increased the exposure to several CYP2C8 substrates such as cerivastatin, repaglinide, pioglitazone, montelukast, and dasabuvir (Backman et al, 2002(Backman et al, , 2016Niemi et al, 2003;Jaakkola et al, 2005;Karonen et al, 2010;Tornio et al, 2014;Itkonen et al, 2016Itkonen et al, , 2018Itkonen et al, , 2019. Recently, both clopidogrel and gemfibrozil were suggested as model CYP2C8 inhibitors for DDI studies in the FDA Draft Guidance for Clinical Drug Interaction Studies (https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf).…”

Emergence of institutional antithrombotic protocols for coronavirus 2019

“…Several protocol strategies take into consideration the concomitant use of antithrombotic with antiviral therapies (especially with the antivirals liponavir and ritonavir), as this can affect choice and/or dosage of antiplatelet and anticoagulants. For antiplatelet agents, certain antivirals, especially lopinavir/ritonavir, may potentiate CYP3A4 or P‐gp inhibition, and as such there may be reduction in clopidogrel effects and increased effects of ticagrelor 52,53 . Therefore, these agents should be switched over to prasugrel if possible (unless there are contraindications such as prior stroke or transient ischemic attack) 53 .…”

Managing ACS during COVID-19 infection: Do not follow the traditional route

“…3 Conversely, clopidogrel may not provide sufficient platelet inhibition during concomitant administration of lopinavir/ritonavir but this was not the case with prasugrel. 13,14 In case prasugrel cannot be used, testing guided approach with platelet function assays is strongly recommended. 11.…”