Effect of co-medications and potential risk factors of high-dose methotrexate-mediated acute hepatotoxicity in patients with osteosarcoma

Sheng-Fan Wang; Kuan-Wei Huang; Yueh-Ching Chou; Hsin-Chen Lee; Po-Kuei Wu; Wei-Ming Chen; Giun-Yi Hung; Yuh-Lih Chang

doi:10.1002/cam4.5936

Effect of co-medications and potential risk factors of high-dose methotrexate-mediated acute hepatotoxicity in patients with osteosarcoma

Cancer Med. 2023 Jun;12(11):12354-12364. doi: 10.1002/cam4.5936. Epub 2023 Apr 16.

Authors

Sheng-Fan Wang^{1

2

3}, Kuan-Wei Huang², Yueh-Ching Chou^{1

2

3

4}, Hsin-Chen Lee^{2

4}, Po-Kuei Wu^{5

6

7

8}, Wei-Ming Chen^{5

6

7

8}, Giun-Yi Hung^{9

10}, Yuh-Lih Chang^{1

2

4}

Affiliations

¹ Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan.
² Department and Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
³ Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
⁴ Department of Pharmacy, School of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁵ Department of Orthopedics and Joint Reconstruction, Taipei Veterans General Hospital, Taipei, Taiwan.
⁶ Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan.
⁷ Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁸ Orthopedic Department of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁹ Division of Pediatric Hematology and Oncology, Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁰ School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.

Abstract

Background: Taiwanese patients frequently experience severe hepatotoxicity associated with high-dose methotrexate (HD-MTX) treatment, which interferes with subsequent treatment. Drug-drug interactions occur when MTX is used in combination with proton pump inhibitors (PPIs), trimethoprim-sulfamethoxazole (TMP-SMX), or non-steroidal anti-inflammatory drugs (NSAIDs). In East Asia, real-world analyses on the effects of co-medication and other potential risk factors on the clinical course of HD-MTX-mediated acute hepatotoxicity in patients with osteogenic sarcoma (OGS) are limited.

Methods: This cohort study included patients with newly diagnosed OGS who were treated with HD-MTX between 2009 and 2017 at Taipei Veterans General Hospital. We collected data on the clinical course of HD-MTX-mediated acute hepatotoxicity, co-medications, and other potential risk factors, and analyzed the effects of these factors on the clinical course of HD-MTX-mediated acute hepatotoxicity.

Results: Almost all patients with OGS treated with HD-MTX developed acute hepatotoxicity with elevated alanine aminotransferase (ALT) levels. Most patients with Grade 3-4 ALT elevation failed to recover to Grade 2 within 7 days. Women and children are high-risk subgroups for HD-MTX-mediated elevation of ALT levels. Age is a factor that contributes to the pharmacokinetic differences of HD-MTX. However, the concurrent use of PPIs, TMP-SMX, or NSAIDs did not affect the elimination of MTX when administered with adequate supportive therapy.

Conclusions: Co-administration of PPIs, TMP-SMX, or NSAIDs may have limited effects on acute hepatotoxicity in well-monitored and adequately pre-medicated patients with OGS undergoing chemotherapy with HD-MTX. Clinicians should pay particular attention to ALT levels when prescribing HD-MTX to children and women.

Keywords: hepatotoxicity; high-dose methotrexate; non-steroidal anti-inflammatory drugs; osteosarcoma; proton pump inhibitors; trimethoprim-sulfamethoxazole.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal
Bone Neoplasms* / drug therapy
Chemical and Drug Induced Liver Injury* / diagnosis
Chemical and Drug Induced Liver Injury* / drug therapy
Chemical and Drug Induced Liver Injury* / etiology
Child
Cohort Studies
Disease Progression
Female
Humans
Methotrexate
Osteosarcoma* / drug therapy
Proton Pump Inhibitors / therapeutic use
Risk Factors
Trimethoprim, Sulfamethoxazole Drug Combination / adverse effects

Substances

Methotrexate
Trimethoprim, Sulfamethoxazole Drug Combination
Anti-Inflammatory Agents, Non-Steroidal
Proton Pump Inhibitors