Cardiovascular Drugs and Therapy ( IF 3.1 ) Pub Date : 2023-12-19 , DOI: 10.1007/s10557-023-07538-w Evelyn Krohmer 1 , Brit Silja Rohr 1 , Felicitas Stoll 1 , Katja S Gümüs 1 , Mariano Bergamino 1 , Gerd Mikus 1 , Max Sauter 1 , Jürgen Burhenne 1 , Johanna Weiss 1 , Andreas D Meid 1 , David Czock 1 , Antje Blank 1 , Walter E Haefeli 1
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Purpose
Early antiviral treatment with nirmatrelvir/ritonavir is recommended for SARS-CoV-2-infected patients at high risk for severe courses. Such patients are usually chronically ill and susceptible to adverse drug interactions caused by ritonavir. We investigated the interactions of short-term low-dose ritonavir therapy with atorvastatin and rosuvastatin, two statins commonly used in this population.
Method
We assessed exposure changes (area under the concentration–time curve (AUC∞) and maximum concentration (Cmax)) of a single dose of 10 mg atorvastatin and 10 mg rosuvastatin before and on the fifth day of ritonavir treatment (2 × 100 mg/day) in healthy volunteers and developed a semi-mechanistic pharmacokinetic model to estimate dose adjustment of atorvastatin during ritonavir treatment.
Results
By the fifth day of ritonavir treatment, the AUC∞ of atorvastatin increased 4.76-fold and Cmax 3.78-fold, and concurrently, the concentration of atorvastatin metabolites decreased to values below the lower limit of quantification. Pharmacokinetic modelling indicated that a stepwise reduction in atorvastatin dose during ritonavir treatment with a stepwise increase up to 4 days after ritonavir discontinuation can keep atorvastatin exposure within safe and effective margins. Rosuvastatin pharmacokinetics were only mildly modified; ritonavir significantly increased the Cmax 1.94-fold, while AUC∞ was unchanged.
Conclusion
Atorvastatin doses should likely be adjusted during nirmatrelvir/ritonavir treatment. For patients on a 20-mg dose, we recommend half of the original dose. In patients taking 40 mg or more, a quarter of the dose should be taken until 2 days after discontinuation of nirmatrelvir/ritonavir. Patients receiving rosuvastatin do not need to change their treatment regimen.
Trial Registration
EudraCT number: 2021–006634-39.
DRKS00027838.
中文翻译：
短期利托那韦作为 SARS-CoV-2 抗病毒治疗中的加强剂对阿托伐他汀和瑞舒伐他汀暴露的影响
目的
建议对重度病程高风险的 SARS-CoV-2 感染患者进行早期抗病毒治疗。此类患者通常患有慢性病，并且容易受到利托那韦引起的不良药物相互作用的影响。我们研究了短期低剂量利托那韦治疗与阿托伐他汀和瑞舒伐他汀（该人群常用的两种他汀类药物）的相互作用。
方法
我们评估了利托那韦治疗前和第五天单剂量 10 mg 阿托伐他汀和 10 mg 瑞舒伐他汀的暴露变化（浓度-时间曲线下面积 (AUC ∞ ) 和最大浓度 ( C max )）（2 × 100 mg /天）在健康志愿者中进行，并开发了半机械药代动力学模型来估计利托那韦治疗期间阿托伐他汀的剂量调整。
结果
到利托那韦治疗第五天，阿托伐他汀的 AUC ∞增加了 4.76 倍， C max 增加了3.78 倍，同时，阿托伐他汀代谢物的浓度降至低于定量下限的值。药代动力学模型表明，在利托那韦治疗期间逐步减少阿托伐他汀剂量，并在利托那韦停药后最多 4 天逐步增加阿托伐他汀剂量，可以将阿托伐他汀暴露量保持在安全有效的范围内。瑞舒伐他汀的药代动力学仅进行了轻微修改；利托那韦显着增加C max 1.94 倍，而 AUC ∞不变。
结论
在尼马曲韦/利托那韦治疗期间，阿托伐他汀剂量可能需要调整。对于服用 20 毫克剂量的患者，我们建议使用原始剂量的一半。对于服用 40 mg 或更多剂量的患者，应服用四分之一剂量，直至停药后 2 天。接受瑞舒伐他汀治疗的患者无需改变治疗方案。
试用注册
EudraCT 编号：2021–006634-39。
DRKS00027838。
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