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

Figures

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  Figure 1. Study design. Twelve healthy individuals ingested as pretreatment either placebo (PLC), or clopidogrel (CLOP; 300 mg on day 3 followed by 75 mg on days 4 and 5 at 8.00 am) for 3 days; or ritonavir (RTV; 100 twice daily at 8.00 am and pm) for 5 days; or both ritonavir for 5 and clopidogrel for 3 days. On day 3 of each phase, the volunteers were administered 250 mg of dasabuvir (DAS) at 9.00 am.

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  Figure 2. The effect of ritonavir (100 mg twice daily on days 1–5), clopidogrel (300 mg on day 3, followed by 75 mg on days 4 and 5), and their combination (ritonavir 100 mg twice daily on days 1–5, and clopidogrel 300 mg on day 3 and 75 mg on days 4 and 5) on the plasma concentrations of dasabuvir (a), and its M1 metabolite (b). On day 3 of each of the four phases, including placebo phase, dasabuvir (250 mg) was administered to 12 healthy individuals 1 hour after the morning dose of pretreatment. Data are presented as geometric means with 90% CI. For clarity, some error bars have been omitted. Insets depict the same data on a semilogarithmic scale.

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  Figure 3. The individual area under the plasma concentration time curve from zero to infinity (AUC0‐∞) of dasabuvir in placebo and clopidogrel phases (a), and in ritonavir and clopidogrel–ritonavir phases (b) in 12 healthy subjects after ingestion of 250 mg of dasabuvir in a crossover study during the four study phases. Dasabuvir (250 mg) was administered on the day 3, 1 hour after the morning pretreatment with placebo, clopidogrel, ritonavir, or clopidogrel–ritonavir.

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  Figure 4. The plasma concentrations of clopidogrel (a), clopidogrel active cis‐5‐thiol metabolite (b), clopidogrel carboxylic acid (c), and clopidogrel acyl‐β‐D‐glucuronide (d), and the percent inhibition of platelet aggregation (e) after clopidogrel 300 mg with and without ritonavir 100 mg twice a day initiated 2 days before clopidogrel administration. In addition, the plasma concentrations of ritonavir (f) after the fifth 100 mg ritonavir dose with and without clopidogrel 300 mg in the morning of day 3 are shown. A single oral dose of 250 mg dasabuvir was administered 1 hour after the morning dose of clopidogrel, ritonavir, and their combination. Data are presented as geometric means (except for the mean percent inhibition of platelet aggregation, which are given as arithmetic means) with 90% CI. For clarity, some error bars have been omitted.