Department of Pharmacy, Ibaraki Prefectural Central Hospital, Koibuchi 6528, Kasama, Ibaraki, 309-1973, Japan.
Department of Medical Oncology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan.
Cancer Chemother Pharmacol. 2024 Jun;93(6):633-638. doi: 10.1007/s00280-023-04628-2. Epub 2023 Dec 26.
Guidelines such as the National Comprehensive Cancer Network recommend mycophenolate mofetil (MMF) for the treatment of severe steroid-refractory immune-related hepatotoxicity. Mycophenolic acid (MPA) is an active form of MMF that suppresses T- and B-lymphocyte proliferation and immune-related adverse events caused by immune checkpoint inhibitors. MPA has a narrow therapeutic range (37-70 µg·h/mL) and overexposure increases the risk of leukopenia in transplantation. However, the optimal use of MMF in oncology has not yet been established; thus, monitoring plasma MPA concentrations is necessary to avoid excessive immunosuppression in oncology practice.
We evaluated plasma MPA concentration in a 75-year-old man with immune-related hepatotoxicity following nivolumab and ipilimumab combination therapy for malignant melanoma. The patient developed severe hepatotoxicity after immunotherapy, and immunosuppressant therapy with corticosteroids was initiated. The patient then developed steroid-refractory immune-related hepatotoxicity; therefore, MMF (1,000 mg twice daily) was co-administered. Seven days after the administration of MMF, the plasma MPA concentration was measured using an enzyme multiplied immunoassay technique. The area under the plasma concentration-time curve for MPA from 0 to 12 h was 41.0 µg·h/mL, and the same dose of MMF was continued. Grade 2 lymphocytopenia, which could be attributed to MMF, was observed during the administration period. Unfortunately, the patient was infected with SARS-CoV-2 and died from respiratory failure.
Our patient did not exceed the upper limit of MPA levels as an index of the onset of side effects of kidney transplantation and achieved rapid improvement in liver function. Prompt initiation of MMF after assessment of the steroid effect leads to adequate MPA exposure. Therapeutic drug monitoring should be considered when MMF is administered, to avoid overexposure.
国家综合癌症网络等指南建议使用吗替麦考酚酯（MMF）治疗严重的类固醇难治性免疫相关肝毒性。霉酚酸（MPA）是 MMF 的一种活性形式，可抑制 T 和 B 淋巴细胞增殖以及免疫检查点抑制剂引起的免疫相关不良事件。MPA 的治疗窗较窄（37-70μg·h/mL），药物过量会增加移植后白细胞减少的风险。然而，MMF 在肿瘤学中的最佳应用尚未确定；因此，在肿瘤学实践中需要监测血浆 MPA 浓度，以避免过度免疫抑制。
我们评估了一名 75 岁男性患者的血浆 MPA 浓度，该患者在接受纳武单抗和伊匹单抗联合治疗恶性黑色素瘤后出现免疫相关肝毒性。该患者在免疫治疗后发生严重肝毒性，并开始接受皮质类固醇免疫抑制剂治疗。随后，该患者发生类固醇难治性免疫相关肝毒性，因此给予 MMF（1000mg，每日两次）联合治疗。在给予 MMF 治疗 7 天后，采用酶放大免疫测定技术测定血浆 MPA 浓度。MPA 从 0 到 12 小时的药时曲线下面积为 41.0μg·h/mL，继续给予相同剂量的 MMF。在给药期间观察到可能归因于 MMF 的 2 级淋巴细胞减少症。不幸的是，该患者感染了 SARS-CoV-2 并因呼吸衰竭而死亡。
我们的患者没有超过 MMF 作为移植后副作用发生指标的上限水平，并且肝功能迅速改善。在评估类固醇效应后及时开始 MMF 治疗可实现充分的 MPA 暴露。当给予 MMF 时应考虑治疗药物监测，以避免药物过量。
