Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.
Clin Pharmacol Ther. 2022 Oct;112(4):803-807. doi: 10.1002/cpt.2687. Epub 2022 Jul 4.
Patients with coronavirus disease 2019 (COVID-19) with cardiovascular diseases who are at higher risk of progressing to critical illness should be treated with nirmatrelvir/ritonavir (Paxlovid). Ritonavir, the booster in nirmatrelvir/ritonavir, modulates multiple drug metabolizing enzymes and transporters, complicating its use in real-world clinics. We aimed to apply physiologically-based pharmacokinetic (PBPK) modeling to simulate the complex drug-drug interactions (DDIs) of ritonavir with two anticoagulants, rivaroxaban and racemic warfarin, to address this important clinical conundrum. Simulations were implemented within Simcyp Simulator. Compound and population models were adopted from Simcyp and our previous studies. Upon verification and validation of the PBPK model of ritonavir, prospective DDI simulations with the anticoagulants were performed in both the general population (20-65 years) and geriatric subjects (65-85 years) with or without moderate renal impairment. Elevated rivaroxaban concentrations were simulated with nirmatrelvir/ritonavir treatment, where the impact was more profound among geriatric subjects with renal impairment. The overexposure of rivaroxaban was restored to normal range on day 4 post-discontinuation of nirmatrelvir/ritonavir, corroborating with the recovery of enzyme activity. A lower 10 mg daily dose of rivaroxaban could effectively maintain acceptable systemic exposure of rivaroxaban during nirmatrelvir/ritonavir treatment. Treatment of ritonavir marginally declined simulated S-warfarin concentrations, but substantially elevated that of R-warfarin, resulting in a decrease in the international normalized ratio (INR). As INR only recovered 2 weeks post-nirmatrelvir/ritonavir treatment, a longer surveillance INR for warfarin becomes important. Our PBPK-guided simulations evaluated clinically important yet untested DDIs and supports clinical studies to ensure proper anticoagulation management of patients with COVID-19 with chronic coagulative abnormalities when initiating nirmatrelvir/ritonavir therapy.
新型冠状病毒病 2019（COVID-19）伴有心血管疾病的患者，进展为危重症的风险较高，应使用奈玛特韦/利托那韦（Paxlovid）治疗。利托那韦是奈玛特韦/利托那韦中的增效剂，可调节多种药物代谢酶和转运体，使其在真实临床环境中的应用变得复杂。我们旨在应用基于生理学的药代动力学（PBPK）模型来模拟利托那韦与两种抗凝剂（利伐沙班和消旋华法林）的复杂药物相互作用（DDI），以解决这一重要的临床难题。模拟在 Simcyp Simulator 中进行。采用来自 Simcyp 和我们之前研究的化合物和群体模型。在验证和验证利托那韦 PBPK 模型后，在普通人群（20-65 岁）和老年人群（65-85 岁）中进行了与抗凝剂的前瞻性 DDI 模拟，无论是否存在中度肾功能损害。在接受奈玛特韦/利托那韦治疗时，模拟出利伐沙班浓度升高，肾功能损害的老年患者影响更为明显。在停止奈玛特韦/利托那韦治疗后第 4 天，利伐沙班的暴露量恢复正常范围，这与酶活性的恢复相符。利伐沙班的较低每日 10mg 剂量可在奈玛特韦/利托那韦治疗期间有效维持可接受的利伐沙班系统暴露量。利托那韦治疗使模拟的 S-华法林浓度略有下降，但显著升高 R-华法林的浓度，导致国际标准化比值（INR）降低。由于奈玛特韦/利托那韦治疗后 INR 仅在 2 周后恢复，因此对华法林的更长时间监测 INR 变得重要。我们的 PBPK 指导模拟评估了具有临床重要性但未经测试的 DDI，并支持临床研究，以确保在 COVID-19 患者因慢性凝血异常而开始使用奈玛特韦/利托那韦治疗时，对抗凝治疗进行适当管理。
