Long-Term Safety Profile of Sirolimus In Children and Adults: A Pooled Analysis of Two 10-Year Cohort Studies Comprising

Background: Evidence on long-term safety profile of sirolimus in all-age patients, especially children, is still not enough. Methods: This is a pooled analysis of two 10-year prospective cohort studies. A total of 1738 patients aged from 5 days to 69 years with tuberous sclerosis (TSC) and/or lymphangioleiomyomatosis(LAM) were recruited. All patients had no history of taking any mTOR inhibitors before enrollment. Patients were administered 1 mg/(m2.d) sirolimus oral solution or tablet. Dose adjustments were made by a 2-week titration period to attain a trough blood concentration of 5 to 10 ng/ml. The maximum dose is 2mg. Indicators of physical growth (height only for pediatric patients), hematopoietic, liver, and renal function, as well as blood lipid levels, were all primary outcomes. GLM analysis and Chi-square test were used to reveal the changes between the baseline and follow-up periods. Four models with cross-validation were constructed for further analysis of the relationship between changes and demographic features. Results: Compared with the baseline level, no abnormal results reaching significant differences were observed in hematopoietic, liver, and renal function. Z scores of height, weight, and BMI increased significantly throughout the follow-up, and the dose of sirolimus was the only related factor. Also, the frequently reported hyperlipidemia mainly occurred in the first six months and was overall mild. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5%. Conclusions: Sirolimus was overall with higher tolerability. For the first time, benefits in physical growth in pediatric patients were observed.