202206201202COVID-19 藥物交互作用 Paxlovid versus plavix(Clopidogrel)

Paxlovid 與其他藥物交互作用 Drug-Drug Interaction(DDI)
若有高血栓風險不建議同時使用, 例如剛裝心臟支架六周內
若因其他狀況無法使用aspirin, 而將 clopidogrel 作為替代藥物, 此時若短期內(五天)同時服用 paxlovid, 病患發生血栓風險小於用藥的效益, 可考慮同時使用

過去曾研究.  ritonavir-boosted HIV protease inhibitors 與 Clopidogrel同時使用, 會降低 Clopidogrel 活性代謝物濃度(降低 Clopidogrel 療效), 
More InfoQuality of Evidence: Very Low
Summary:Coadministration with nirmatrelvir/ritonavir has not been studied but is likely to reduce the effect of clopidogrel.
Coadministration should be avoided in patients at very high-risk of thrombosis, e.g. at least within 6 weeks of coronary stenting. However, other conditions (e.g. clopidogrel used as an alternative to aspirin in intolerant patients or when used outside the critical period post coronary stenting associated with a higher risk of coronary artery stent thrombosis) may tolerate a reduced effect for the short duration of nirmatrelvir/ritonavir treatment and it may be possible to maintain some patients on clopidogrel during treatment with nirmatrelvir/ritonavir. Clopidogrel is a prodrug and is converted to its active metabolite via CYPs 3A4, 2B6, 2C19 and 1A2. Coadministration of clopidogrel and ritonavir-boosted HIV protease inhibitors has been evaluated in clinical studies and showed that ritonavir decreased the AUC and Cmax of clopidogrel’s active metabolite. Importantly, the decrease in clopidogrel’s active metabolite lead to insufficient inhibition of platelet aggregation in 44% of the patients treated with clopidogrel and ritonavir. The inhibition of platelet aggregation has been shown to be unaltered when prasugrel was coadministered with ritonavir; therefore, prasugrel could be used with nirmatrelvir/ritonavir. The management of this interaction requires to take into account whether or not a transient loss of clopidogrel efficacy during the short duration of nirmatrelvir/ritonavir treatment is acceptable. The initial period (at least 6 weeks) post coronary stenting represents a high-risk situation which does typically warrant a transition to prasugrel or, if this is not possible, an alternative COVID-19 treatment should be considered. However, a transient loss in efficacy (and therefore maintaining clopidogrel treatment) may be acceptable for other clinical situations.Description:

The impact of boosted antiretroviral therapies on the pharmacokinetics of clopidogrel and prasugrel active metabolites (AM) and on the efficacy of prasugrel and clopidogrel were evaluated in a randomized crossover study. A significantly lower exposure of clopidogrel AM (69% decrease) and prasugrel AM (52% decrease) were demonstrated in HIV-infected patients treated sequentially with a loading dose of clopidogrel (300 mg) and prasugrel (60 mg) while on a ritonavir- or cobicistat- containing antiretroviral regimen compared to healthy volunteers receiving only the corresponding antiplatelet agent. Of interest, the coadministration with ritonavir or cobicistat had a differential impact on clopidogrel and prasugrel pharmacodynamics effect. Treatment with clopidogrel resulted in adequate platelet inhibition in all healthy volunteers (no coadministration of ritonavir- or cobicistat-boosted regimens) while 44% of HIV-infected patients were shown to have insufficient platelet inhibition (coadministration with ritonavir- or cobicistat-boosted regimens). On the contrary, treatment with prasugrel resulted in a potent platelet inhibition in both healthy and HIV-infected subjects. The authors conclude that prasugrel remains an adequate antiplatelet agent in HIV-infected patients and could be preferred to clopidogrel in this context, regardless of the metabolic interaction and inhibition of its bioactivation pathways.
Impact of boosted antiretroviral therapy on the pharmacokinetics and efficacy of clopidogrel and prasugrel active metabolites. Marsousi N, Daali Y, Fontana P, et al. Clin Pharmacokinet, 2018, 57(10):1347-1354.

The impact of ritonavir on the pharmacokinetics of clopidogrel active metabolite (AM) and the pharmacodynamic effect was evaluated in a randomized, placebo-controlled, crossover study in 12 healthy volunteers. Subjects ingested either placebo or clopidogrel (300 mg followed by 75 mg the two following days) alone and together with ritonavir (100 mg twice daily). Ritonavir significantly decreased the exposure of clopidogrel AM by 51% and average platelet inhibition significantly decreased from 51% without ritonavir to 31% with ritonavir (mean difference 90% CI -27% to -12%). The maximal platelet inhibition by clopidogrel was also reduced from 60% to 40% during concurrent ritonavir (mean difference 90% CI -29% to -11%). The authors conclude that patients receiving ritonavir are at risk for diminished clopidogrel response and consequently increased risk for atherothrombotic events if the two drugs are used concurrently. The authors recommend to avoid concomitant administration of clopidogrel with ritonavir.
Clopidogrel increases dasabuvir exposure with or without ritonavir, and ritonavir inhibits the bioactivation of clopidogrel. Itkonen MK, Tornio A, Lapatto-Reiniluoto O, et al. Clin Pharmacol Ther, 2019, 105(1):219-228.