Hewlett Jennifer L, Goka Selasie, Nwaogazie Uche, Finkel Rachel, Galea Lauren, Lopez Sonya, Laskin Benjamin, LaRosa Christopher, Downes Kevin J, Amaral Sandra, Savant Jonathan D, Viteri Bernarda
Department of Pharmacy, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Pediatr Transplant. 2025 May;29(3):e70030. doi: 10.1111/petr.70030.
Paxlovid, a fixed combination nirmatrelvir and ritonavir (NIM-RTV), is a potent inhibitor of cytochrome P450 3A4 (CYP3A4) isoenzyme. It is approved for the treatment of mild to moderate COVID-19 infections in patients at risk for serious infection. The metabolism of tacrolimus, a CYP3A4 substrate, is significantly reduced in those receiving NIM-RTV. Coadministration of NIM-RTV without tacrolimus dose reduction may result in toxicity. CYP3A4-inducing medications, including phenytoin, fosphenytoin or rifampin, may reverse toxicity while achieving rapid clearance.
A 14-year-old, 66.5 kg African American female with a history of chronic kidney disease stage 5 secondary to collapsing focal segmental glomerulosclerosis (FSGS) underwent an uncomplicated deceased donor kidney transplant at 12 years of age. Approximately 2.5 years after transplant, she tested positive for COVID-19. NIM-RTV was prescribed through a local pharmacy. She presented 3.5 days later with nausea, vomiting, fatigue, and oligo-anuria with acute kidney injury (AKI) and creatinine of 2.6 mg/dL from baseline of 0.7 mg/dL. Tacrolimus level was > 60 ng/mL. Phenytoin/fosphenytoin was initiated to induce tacrolimus clearance due to sustained AKI and neurological risk. Within 36 h, her tacrolimus level was 38 ng/mLwith improved urine output. After 3 days, her tacrolimus level 11.9 ng/mL and serum creatinine was near baseline.
To our knowledge, this is the first report of a pediatric kidney transplant patient with tacrolimus toxicity secondary to NIM-RTV therapy utilizing phenytoin/fosphenytoin to induce tacrolimus metabolism and prevent further toxicity. Heightened awareness of this interaction is paramount to reduce allograft injury and promote patient safety.
帕罗韦德（Paxlovid）是一种由奈玛特韦和利托那韦（NIM-RTV）组成的固定剂量复方制剂，是细胞色素P450 3A4（CYP3A4）同工酶的强效抑制剂。它被批准用于治疗有严重感染风险的轻度至中度新冠病毒感染患者。他克莫司是CYP3A4的底物，在接受NIM-RTV治疗的患者中，其代谢显著降低。在不降低他克莫司剂量的情况下合用NIM-RTV可能会导致毒性。包括苯妥英、磷苯妥英或利福平在内的CYP3A4诱导药物，可在实现快速清除的同时逆转毒性。
一名14岁、体重66.5千克的非裔美国女性，有因塌陷性局灶节段性肾小球硬化（FSGS）继发的慢性肾脏病5期病史，12岁时接受了一次无并发症的已故供体肾移植。移植后约2.5年，她的新冠病毒检测呈阳性。通过当地药房开具了NIM-RTV。3.5天后，她出现恶心、呕吐、疲劳和少尿性急性肾损伤（AKI），肌酐从基线的0.7毫克/分升降至2.6毫克/分升。他克莫司水平>60纳克/毫升。由于持续的急性肾损伤和神经学风险，开始使用苯妥英/磷苯妥英来促进他克莫司清除。在36小时内，她的他克莫司水平降至38纳克/毫升，尿量有所改善。3天后，她的他克莫司水平为11.9纳克/毫升，血清肌酐接近基线水平。
据我们所知，这是首例关于小儿肾移植患者因NIM-RTV治疗继发他克莫司毒性，使用苯妥英/磷苯妥英诱导他克莫司代谢并预防进一步毒性的报告。提高对这种相互作用的认识对于减少移植肾损伤和促进患者安全至关重要。
