Teimori Kaveh, Larsen Bjarke Strøm, Austli Mathias Buaas, Nilsson Niklas, Tho Ingunn, Nezvalova-Henriksen Katerina
Oslo Hospital Pharmacy, Hospital Pharmacies Enterprise, South-Eastern Norway, 0372 Oslo, Norway.
Department of Pharmacy, University of Oslo, 0316 Oslo, Norway.
Pharmaceutics. 2025 Sep 3;17(9):1155. doi: 10.3390/pharmaceutics17091155.
: Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer requiring cytotoxic methotrexate treatment. This always necessitates intravenous administration of rescue therapy consisting of calcium folinate and bicarbonate. Current recommendations advise against mixing these two drugs due to concerns regarding precipitate formation of calcium carbonate (CaCO) that could result in catheter and capillary obstruction. These recommendations are based on drug concentrations not clinically relevant in pediatric ALL settings. Our study investigated the effect of clinically relevant calcium folinate-bicarbonate concentrations on the risk of CaCO precipitation. : A theoretical prediction model provided estimates of final mixing concentrations in five scenarios: three simulated pediatric patient models (approx. 1, 9, and 14 years), an undiluted drug mix, and a high-risk control outlier case. Physical compatibility tests were conducted using validated methods for particle detection, complemented by Raman spectroscopy for particle identification. : Theoretical predictions suggested CaCO precipitation with elevated bicarbonate concentrations and pH levels. Our simulated patient models and high-risk control outlier case showed that CaCO precipitation may be avoided below certain serum methotrexate concentrations and thereby calcium folinate and bicarbonate concentrations. Physical testing demonstrated particle formation only in the undiluted mix with Raman spectroscopy confirming the finding. : Mixing calcium folinate and bicarbonate appears safe under specific methotrexate-directed pediatric ALL treatment conditions. While high bicarbonate concentrations pose precipitation risks, protocol-based dosing regimens mitigate this. Switching to disodium folinate or using in-line filters could further enhance co-administration safety if bicarbonate concentrations exceed the safety limit suggested by our results.
急性淋巴细胞白血病（ALL）是最常见的需要进行细胞毒性甲氨蝶呤治疗的儿童癌症。这总是需要静脉注射由亚叶酸钙和碳酸氢盐组成的救援疗法。由于担心碳酸钙（CaCO）沉淀可能导致导管和毛细血管阻塞，目前的建议是不要将这两种药物混合使用。这些建议是基于儿科ALL环境中与临床无关的药物浓度。我们的研究调查了临床相关的亚叶酸钙 - 碳酸氢盐浓度对CaCO沉淀风险的影响。
三种模拟的儿科患者模型（约1、9和14岁）、未稀释的药物混合物以及一个高风险对照异常案例。使用经过验证的颗粒检测方法进行物理相容性测试，并辅以拉曼光谱法进行颗粒鉴定。
理论预测表明，随着碳酸氢盐浓度和pH值升高会出现CaCO沉淀。我们的模拟患者模型和高风险对照异常案例表明，在某些血清甲氨蝶呤浓度以及由此产生的亚叶酸钙和碳酸氢盐浓度以下，可以避免CaCO沉淀。物理测试表明仅在未稀释的混合物中形成颗粒，拉曼光谱法证实了这一发现。
在特定的甲氨蝶呤指导的儿科ALL治疗条件下，混合亚叶酸钙和碳酸氢盐似乎是安全的。虽然高碳酸氢盐浓度存在沉淀风险，但基于方案的给药方案可减轻这种情况。如果碳酸氢盐浓度超过我们结果所建议的安全限度，改用亚叶酸二钠或使用在线过滤器可进一步提高联合给药的安全性。
