Miyata Yuki, Yamaguchi Ryo, Yamamoto Takehito, Kishida Toshiyuki, Ikeuchi Kazuhiko, Harada Hiroaki, Tsutsumi Takeya, Fujio Keishi, Takada Tappei
Department of Pharmacy, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan.
Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan.
J Pharm Health Care Sci. 2025 Jan 22;11(1):3. doi: 10.1186/s40780-025-00411-y.
Ensitrelvir is a novel SARS-CoV-2 3-chymotrypsin-like protease inhibitor, similar to nirmatrelvir/ritonavir. Several case reports have demonstrated the efficacy of 3-chymotrypsin-like protease inhibitors in treating prolonged coronavirus disease 2019 (COVID-19) in immunocompromised patients. Tacrolimus (TAC) is a widely used immunosuppressive agent whose blood level can increase significantly due to the inhibition of cytochrome P450 3A (CYP3A) and P-glycoprotein by nirmatrelvir/ritonavir. Since ensitrelvir also inhibits CYP3A and P-gp, similar elevations in TAC levels are expected. A prior case report observed an increase in TAC trough levels with concurrent administration of ensitrelvir. However, no studies have quantitatively described the changes in TAC blood levels and clearances before and after ensitrelvir administration when TAC administration was discontinued to mitigate the drug-drug interaction (DDI) risk; data on safe dosing protocols to avoid the DDI during co-administration of ensitrelvir and TAC remain lacking. Here, we report a case in which TAC levels were successfully managed in a patient with rheumatoid arthritis (RA) who received ensitrelvir for persistent COVID-19 by preemptive discontinuation of TAC and close monitoring of TAC blood levels following ensitrelvir administration.
An 81-year-old Japanese woman who had been administered TAC (1.5 mg once daily) for RA received two courses of remdesivir for moderate COVID-19. However, her viral load remained high and her respiratory status deteriorated. Considering persistent COVID-19, we initiated combination therapy with remdesivir and ensitrelvir (day 0). TAC was discontinued, and the TAC blood levels decreased from 3.6 ng/mL to 1.1 ng/mL over five days. Subsequently, we re-administered TAC (0.2 mg), observing a level of 1.0 ng/mL by day 7. The TAC dose was adjusted to 1.0 mg daily, and TAC levels on day 12 and 14 were 6.5 and 3.7 ng/mL, respectively. TAC (1.5 mg daily) was resumed on day 15. The calculated t of TAC were 33.7, 71.9, and 114.6 h from day -1 to 0, day 0 to 2, and day 2 to 5, respectively. The t of TAC was extended to 3.4-fold its original duration under ensitrelvir treatment.
This DDI extended the half-life of TAC by approximately 3.4-fold, an effect that gradually diminished over 7 to 10 days. When patients receiving TAC treatment start ensitrelvir therapy, a dose reduction of TAC by approximately one-third to one-fourth is considered appropriate.
恩西瑞韦是一种新型的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）3-糜蛋白酶样蛋白酶抑制剂，与奈玛特韦/利托那韦类似。多项病例报告已证明3-糜蛋白酶样蛋白酶抑制剂在治疗免疫功能低下患者的持续性2019冠状病毒病（COVID-19）方面的疗效。他克莫司（TAC）是一种广泛使用的免疫抑制剂，由于奈玛特韦/利托那韦对细胞色素P450 3A（CYP3A）和P-糖蛋白的抑制作用，其血药浓度可能会显著升高。由于恩西瑞韦也抑制CYP3A和P-糖蛋白，预计TAC水平会有类似的升高。之前的一份病例报告观察到同时使用恩西瑞韦时TAC谷浓度升高。然而，尚无研究定量描述在停用TAC以降低药物相互作用（DDI）风险后，恩西瑞韦给药前后TAC血药浓度和清除率的变化；关于恩西瑞韦和TAC联合给药期间避免DDI的安全给药方案的数据仍然缺乏。在此，我们报告一例类风湿关节炎（RA）患者，该患者因持续性COVID-19接受恩西瑞韦治疗，通过提前停用TAC并在恩西瑞韦给药后密切监测TAC血药浓度，成功控制了TAC水平。
一名81岁的日本女性因RA接受TAC治疗（每日一次，1.5毫克），因中度COVID-19接受了两个疗程的瑞德西韦治疗。然而，她的病毒载量仍然很高，呼吸状况恶化。考虑到COVID-19持续存在，我们开始使用瑞德西韦和恩西瑞韦联合治疗（第0天）。停用TAC，TAC血药浓度在五天内从3.6纳克/毫升降至1.1纳克/毫升。随后，我们重新给予TAC（0.2毫克），到第7天观察到血药浓度为1.0纳克/毫升。将TAC剂量调整为每日1.0毫克，第12天和第14天的TAC血药浓度分别为6.5纳克/毫升和3.7纳克/毫升。第15天恢复每日1.5毫克的TAC治疗。从第-1天到第0天、第0天到第2天以及第2天到第5天，TAC的计算半衰期分别为33.7小时、71.9小时和114.6小时。在恩西瑞韦治疗下，TAC的半衰期延长至原来的3.4倍。
这种药物相互作用使TAC的半衰期延长了约3.4倍，这种作用在7至10天内逐渐减弱。当接受TAC治疗的患者开始恩西瑞韦治疗时，将TAC剂量减少约三分之一至四分之一被认为是合适的。
