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Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
Liver function trends in children with suspected drug-induced hepatocellular injury: A survey using an electronic
Masayoshi Nakakuni1,2, Kosuke Nakano1, Ayano Inui3
1Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan.
Insights
Pediatric drug-induced liver injury (DILI) was assessed using electronic health records. High-risk drugs like methotrexate and cyclophosphamide were linked to liver injury in children, emphasizing monitoring needs.
Area of Science:
- Pediatric Hepatology
- Pharmacovigilance
- Drug Safety
Background:
- Drug-induced liver injury (DILI) is a significant concern, yet pediatric data remains scarce.
- Limited literature exists on DILI specifically within pediatric populations.
Purpose of the Study:
- To evaluate hepatocellular DILI in pediatric patients prescribed potentially hepatotoxic medications.
- To leverage electronic medical records for DILI assessment in children.
Main Methods:
- Utilized the Pediatric Medical Information Collection System (P-MICS), a database from over 40 pediatric centers.
- Identified pediatric patients (<15 years) with ALT levels ≥5x ULN, excluding non-drug-related liver diseases.
- Analyzed prescription data, LiverTox scores for high-risk drugs, and post-event liver function markers (ALT, TB).
Main Results:
- Identified 251 patients prescribed high-risk drugs: methotrexate (n=129), aspirin (n=82), vancomycin (n=58), cyclophosphamide (n=51).
- Methotrexate and cyclophosphamide users showed significant rates of recurrent ALT elevation (approx. 35%); some methotrexate users also had TB elevation.
- Drug discontinuation led to better outcomes (fewer relapses, TB elevations) compared to continued pharmacotherapy.
Conclusions:
- The P-MICS is effective for identifying pediatric DILI and monitoring liver function.
- Highlights significant liver injury risks associated with anticancer drugs in children.
- Demonstrates the value of P-MICS in tracking pediatric drug safety, especially for off-label use.
Background:
Drug-induced liver injury (DILI) is a common adverse drug event with limited pediatric data in the literature. This study aimed to use pediatric electronic medical records to assess hepatocellular DILI in pediatric patients who were prescribed liver-injury-inducing drugs.
Methods:
The Pediatric Medical Information Collection System (P-MICS) is a centralized database integrating electronic medical records from over 40 medical pediatric centers. Pediatric patients in the P-MICS with serum alanine aminotransferase (ALT) levels five or more times the upper limit of normal and who were below 15 years of age were selected. Those with liver diseases unrelated to drug-induced causes were excluded. We identified drugs prescribed 2 to 90 days before the first elevated ALT reading. High-risk liver-injury-causing drugs were determined based on the LiverTox score. We analyzed post-event ALT and total bilirubin levels (TB) and DILI management.
Results:
Of the 817 patients with suspected DILI, 251 were prescribed four drugs identified as high-risk drugs for hepatocellular DILI: methotrexate (n = 129), aspirin (n = 82), vancomycin (n = 58), and cyclophosphamide (n = 51). The median ALT level at the first event was 245 U/L. Approximately 35% of methotrexate users and cyclophosphamide users experienced recurrent ALT elevation. Some methotrexate users also showed TB elevation. Discontinuation of high-risk drugs resulted in fewer relapses and TB elevations than pharmacotherapy.
Conclusions:
The P-MICS effectively identifies pediatric patients with potential liver injury and tracks liver function in those prescribed liver-injury-causing drugs. This study underscores liver injury risks in pediatric anticancer drug users, highlighting the utility of the P-MICS in monitoring off-label drug safety in children.
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