{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:41:28Z","timestamp":1760060488997,"version":"build-2065373602"},"reference-count":102,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"South-Eastern Norway Regional Health Authority","award":["2022095"],"award-info":[{"award-number":["2022095"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: 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 (CaCO3) 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\u2013bicarbonate concentrations on the risk of CaCO3 precipitation. Methods: 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. Results: Theoretical predictions suggested CaCO3 precipitation with elevated bicarbonate concentrations and pH levels. Our simulated patient models and high-risk control outlier case showed that CaCO3 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. Conclusions: 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.<\/jats:p>","DOI":"10.3390\/pharmaceutics17091155","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T12:07:32Z","timestamp":1756901252000},"page":"1155","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Strategies for Assessing Physical Compatibility of Calcium Folinate with Bicarbonate During Methotrexate Rescue Therapy in Pediatric Patients with Acute Lymphoblastic Leukemia"],"prefix":"10.3390","volume":"17","author":[{"given":"Kaveh","family":"Teimori","sequence":"first","affiliation":[{"name":"Oslo Hospital Pharmacy, Hospital Pharmacies Enterprise, South-Eastern Norway, 0372 Oslo, Norway"},{"name":"Department of Pharmacy, University of Oslo, 0316 Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6828-6381","authenticated-orcid":false,"given":"Bjarke Str\u00f8m","family":"Larsen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Oslo, 0316 Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathias Buaas","family":"Austli","sequence":"additional","affiliation":[{"name":"Oslo Hospital Pharmacy, Hospital Pharmacies Enterprise, South-Eastern Norway, 0372 Oslo, Norway"},{"name":"Department of Hematology, Oslo University Hospital, South-Eastern Norway, 0372 Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2047-8058","authenticated-orcid":false,"given":"Niklas","family":"Nilsson","sequence":"additional","affiliation":[{"name":"Oslo Hospital Pharmacy, Hospital Pharmacies Enterprise, South-Eastern Norway, 0372 Oslo, Norway"},{"name":"Department of Hematology, Oslo University Hospital, South-Eastern Norway, 0372 Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4241-4183","authenticated-orcid":false,"given":"Ingunn","family":"Tho","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Oslo, 0316 Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katerina","family":"Nezvalova-Henriksen","sequence":"additional","affiliation":[{"name":"Oslo Hospital Pharmacy, Hospital Pharmacies Enterprise, South-Eastern Norway, 0372 Oslo, Norway"},{"name":"Department of Pharmacy, University of Oslo, 0316 Oslo, Norway"},{"name":"Department of Hematology, Oslo University Hospital, South-Eastern Norway, 0372 Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"ref_1","first-page":"83","article-title":"Childhood and adolescent cancer statistics, 2014","volume":"64","author":"Ward","year":"2014","journal-title":"CA A Cancer J. 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