Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.
Development DMPK, PKPD, Novo Nordisk A/S, Maaløv, Denmark.
Pediatr Blood Cancer. 2019 Jun;66(6):e27637. doi: 10.1002/pbc.27637. Epub 2019 Mar 5.
Severely delayed elimination of methotrexate (MTX) is difficult to predict in patients treated with high-dose MTX (HD-MTX), but it may cause life-threatening toxicity. It has not been defined how an increase in plasma creatinine can be best used as a predictor for severely delayed MTX elimination, thus providing a guide for therapeutic interventions to minimize renal toxicity.
Pharmacokinetic data were retrospectively collected on 218 Danish children with acute lymphoblastic leukemia treated with HD-MTX 5 or 8 g/m on the NOPHO2000 protocol. Moderately delayed MTX elimination was defined as 42-hour plasma MTX ≥ 4.0-9.9 μM, and severely delayed elimination was defined as 42-hour plasma MTX ≥ 10 μM.
Median 42-hour plasma MTX was 0.61 μM (interquartile range, 0.4-1.06 μM). Of 1295 MTX infusions with 5 g/m (n = 140 patients) or 8 g/m (n = 78 patients), 5.1% were severely (1.5%) or moderately (3.6%) delayed. The risk of having delayed elimination was highest in the first of eight infusions with MTX 5 g/m² (7.4% vs 0.0 to 4.1% for subsequent MTX infusions) (P < 0.02). A 25 μM increase or a 1.5-fold increase in plasma creatinine within 36 hours from start of the MTX infusion had a sensitivity of 92% (95% CI, 82%-97%) and a specificity of 85% (95% CI, 83%-87%) for predicting 42-hour MTX ≥4.0 μM.
A 25 μM increase or a 1.5-fold in plasma creatinine within 36 hours after start of an HD-MTX infusion can predict delayed MTX elimination, thus allowing intensification of hydration and alkalization to avoid further renal toxicity and promote the elimination of MTX.
大剂量甲氨蝶呤（HD-MTX）治疗的患者中，MTX 清除严重延迟难以预测，但可能导致危及生命的毒性。尚未确定血浆肌酐升高如何能最好地用作 MTX 清除严重延迟的预测指标，从而为治疗干预提供指导，以最大限度地减少肾毒性。
回顾性收集了 218 例丹麦急性淋巴细胞白血病患儿的药代动力学数据，这些患儿在 NOPHO2000 方案中接受了 5 或 8 g/m 的 HD-MTX 治疗。中度延迟 MTX 消除定义为 42 小时血浆 MTX≥4.0-9.9 μM，严重延迟消除定义为 42 小时血浆 MTX≥10 μM。
中位 42 小时血浆 MTX 为 0.61 μM（四分位距，0.4-1.06 μM）。在 1295 次 5 g/m（n=140 例患者）或 8 g/m（n=78 例患者）的 MTX 输注中，5.1%（1.5%）或中度（3.6%）延迟。MTX 5 g/m² 的前 8 次输注中，延迟消除的风险最高（7.4%，而随后的 MTX 输注中为 0.0 至 4.1%）（P<0.02）。MTX 输注开始后 36 小时内肌酐血浆浓度增加 25 μM 或增加 1.5 倍，预测 42 小时 MTX≥4.0 μM 的敏感性为 92%（95%CI，82%-97%），特异性为 85%（95%CI，83%-87%）。
MTX 输注开始后 36 小时内肌酐血浆浓度增加 25 μM 或增加 1.5 倍可预测 MTX 清除延迟，从而可以加强水化和碱化以避免进一步的肾毒性，并促进 MTX 的清除。
