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Published on: November 8, 2015
Long-term safety and influence on growth in patients receiving sirolimus: a pooled analysis
Yang-Yang Wang1, Li-Ping Zou2,3, Kai-Feng Xu4
1Department of Pediatrics, The First Medical Center of PLA General Hospital, Chinese PLA General Hospital, Beijing, 100853, China.
Insights
Long-term sirolimus use is safe for pediatric growth and organ function, though higher doses may influence growth metrics. Adverse events like stomatitis and hyperlipidemia are manageable.
Area of Science:
- Pharmacology
- Pediatric Medicine
- Oncology
Background:
- Sirolimus targets the mTOR pathway, used for related diseases.
- Long-term safety data, especially in pediatrics, is limited.
- This study addresses sirolimus's long-term safety in diverse age groups.
Purpose of the Study:
- To evaluate the long-term safety of sirolimus.
- To specifically assess its impact on pediatric growth patterns.
- To analyze effects on hematopoietic, liver, and renal function, and lipid levels.
Main Methods:
- Pooled analysis of two prospective cohort studies (10 years).
- 1,738 participants (5 days to 69 years) with TSC and/or LAM.
- Sirolimus 1 mg/m²/day, dose-adjusted for trough levels (5-10 ng/ml).
Main Results:
- No significant adverse effects on pediatric growth, organ function, or lipids.
- Higher doses showed a trend towards increased height, weight, and BMI Z-scores.
- Common adverse events: stomatitis (52.9%), transient cytopenias, hyperlipidemia (first year).
- Menstrual disorders noted in 48.5% of adult females.
Conclusions:
- Long-term sirolimus is safe for pediatric growth and organ function.
- Potential dose-dependent effects on growth warrant further investigation.
- Management strategies for adverse events like stomatitis are crucial.
Background:
Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients.
Methods:
This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded.
Results:
Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217).
Conclusions:
Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration.
Trial Registration:
Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.
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