Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA.
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
Clin Transl Sci. 2022 Jan;15(1):105-117. doi: 10.1111/cts.13125. Epub 2021 Aug 23.
High-dose methotrexate (HDMTX) pharmacokinetics (PKs), including the best estimated glomerular filtration rate (eGFR) equation that reflects methotrexate (MTX) clearance, requires investigation. This prospective, observational, single-center study evaluated adult patients with lymphoma treated with HDMTX. Samples were collected at predefined time points up to 96 h postinfusion. MTX and 7-hydroxy-MTX PKs were estimated by standard noncompartmental analysis. Linear regression determined which serum creatinine- or cystatin C-based eGFR equation best predicted MTX clearance. The 80 included patients had a median (interquartile range [IQR]) age of 68.6 years (IQR 59.2-75.6), 54 (67.5%) were men, and 74 (92.5%) were White. The median (IQR) dose of MTX was 7.6 (IQR 4.8-11.3) grams. Median clearance was similar across three dosing levels at 4.5-5.6 L/h and was consistent with linear PKs. Liver function, weight, age, sex, concomitant chemotherapy, and number of previous MTX doses did not impact clearance. MTX area under the curve (AUC) values varied over a fourfold range and appeared to increase in proportion to the dose. The eGFR (ml/min) equation most closely correlated with MTX clearance in both the entire cohort and after excluding outlier MTX clearance values (r = 0.31 and 0.51, respectively). HDMTX as a 4-h infusion displays high interpatient pharmacokinetic variability. Population PK modeling to optimize MTX AUC attainment requires further evaluation. The cystatin C-based eGFR equation most closely estimated MTX clearance and should be investigated for dosing and monitoring in adults requiring MTX as part of lymphoma management.
高剂量甲氨蝶呤（HDMTX）药代动力学（PKs），包括反映甲氨蝶呤（MTX）清除率的最佳估计肾小球滤过率（eGFR）方程，需要进行研究。这项前瞻性、观察性、单中心研究评估了接受 HDMTX 治疗的淋巴瘤成年患者。在输注后 96 小时内的预设时间点采集样本。通过标准非房室分析估算 MTX 和 7-羟基-MTX 的 PKs。线性回归确定哪种基于血清肌酐或胱抑素 C 的 eGFR 方程最能预测 MTX 清除率。80 例纳入患者的中位（四分位距 [IQR]）年龄为 68.6 岁（IQR 59.2-75.6），54 例（67.5%）为男性，74 例（92.5%）为白人。MTX 的中位（IQR）剂量为 7.6（IQR 4.8-11.3）克。在 4.5-5.6 L/h 的三个剂量水平下，中位清除率相似，与线性 PKs 一致。肝功能、体重、年龄、性别、伴随化疗和 MTX 剂量数均不影响清除率。MTX 曲线下面积（AUC）值变化范围为四倍，似乎与剂量成正比增加。在整个队列和排除异常 MTX 清除值后，eGFR（ml/min）方程与 MTX 清除率的相关性最密切（分别为 r = 0.31 和 0.51）。4 小时输注的 HDMTX 显示出高度的个体间 PK 变异性。需要进一步评估群体 PK 模型以优化 MTX AUC 的实现。基于胱抑素 C 的 eGFR 方程最能估计 MTX 清除率，应在需要 MTX 作为淋巴瘤治疗一部分的成人中进行剂量和监测研究。
