Darcy A Krueger1, Jamie K Capal2, Paolo Curatolo3, Orrin Devinsky4, Kevin Ess5, Michal Tzadok6, Mary K Koenig7, Vinodh Narayanan8, Federico Ramos9, Sergiusz Jozwiak10, Petrus de Vries11, Anna C Jansen12, Michael Wong13, David Mowat14, John Lawson14, Stephanie Bruns2, David Neal Franz2. 1. Department of Neurology, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Electronic address: krueger_darcy@cchmc.org. 2. Department of Neurology, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. 3. Child Neurology and Psychiatry Unit, Systems Medicine Department, University Hospital Tor Vergata, Rome, Italy. 4. Langone Medical Center, New York University, New York, New York, USA. 5. Monroe Carell Jr Children's Hospital, Vanderbilt University Medical Center, Nashville, TN, USA. 6. Pediatric Neurology Unit, Edmond and Lilly Safra Children Hospital, Chaim Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel HaShomer, Tel Aviv, Israel. 7. University of Texas at Houston, Houston, TX, USA. 8. Arizona Pediatric Neurology and Neurogenetics Associates, Phoenix, AZ, USA. 9. Department of Neurology, Sant Joan de Deu Hospital, Barcelona, Spain. 10. Department of Pediatric Neurology, Warsaw Medical University, Poland and Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland. 11. Division of Child & Adolescent Psychiatry, University of Cape Town, Cape Town, South Africa. 12. Pediatric Neurology Unit, UZ Brussel, Brussels, Belgium. 13. Washington University St. Louis, St. Louis, MO, USA. 14. Sydney Children's Hospital, Sydney, Australia.
Abstract
OBJECTIVE: To evaluate the safety of mTOR inhibitors (sirolimus or everolimus) in infants and very young children with tuberous sclerosis complex (TSC) under two years of age. METHODS: Study design was retrospective to capture medical record data from 52 international TSC Centres who initiated treatment with sirolimus or everolimus in TSC children before the age of two years. Data collection included demographic and clinical information including reason(s) for initiating treatment with mTOR inhibitors, treatment duration, dosing, and corresponding serum trough levels, response to treatment, and adverse events (AE). RESULTS: 19 of 52 (37%) TSC Centres reported treatment of at least one child with TSC under the age of two years with everolimus or sirolimus. Treatment-related data were provided for 45 patients meeting inclusion criteria. Everolimus was utilised 87% of the time, compared to 24% for sirolimus (5 subjects, 11%, were treated separately with both). Refractory epilepsy (45%) was the most common primary reason for initiating treatment and treatment was initiated on average at 11.6 ± 7.6 months of age. At least one AE, suspected or definitely treatment-related, occurred in 35 of 45 (78%) treated subjects. Most AEs were mild (Grade 1) or moderate (Grade 2) in severity and most commonly related to infections. Severe AE (Grade 3) was reported in 7 subjects (20%) and no life-threatening AE (Grade 4) or death/disability (Grade 5) was reported. Treatment was discontinued due to an AE in 9 of 45 (20%). CONCLUSIONS: Everolimus, and to a lesser extent sirolimus, are increasingly being used to treat TSC infants and very young children for multiple TSC-associated clinical indications. While AEs were common, most were not severe and did not prevent continued treatment in the majority of this younger population.
OBJECTIVE: To evaluate the safety of mTOR inhibitors (sirolimus or everolimus) in infants and very young children with tuberous sclerosis complex (TSC) under two years of age. METHODS: Study design was retrospective to capture medical record data from 52 international TSC Centres who initiated treatment with sirolimus or everolimus in TSC children before the age of two years. Data collection included demographic and clinical information including reason(s) for initiating treatment with mTOR inhibitors, treatment duration, dosing, and corresponding serum trough levels, response to treatment, and adverse events (AE). RESULTS: 19 of 52 (37%) TSC Centres reported treatment of at least one child with TSC under the age of two years with everolimus or sirolimus. Treatment-related data were provided for 45 patients meeting inclusion criteria. Everolimus was utilised 87% of the time, compared to 24% for sirolimus (5 subjects, 11%, were treated separately with both). Refractory epilepsy (45%) was the most common primary reason for initiating treatment and treatment was initiated on average at 11.6 ± 7.6 months of age. At least one AE, suspected or definitely treatment-related, occurred in 35 of 45 (78%) treated subjects. Most AEs were mild (Grade 1) or moderate (Grade 2) in severity and most commonly related to infections. Severe AE (Grade 3) was reported in 7 subjects (20%) and no life-threatening AE (Grade 4) or death/disability (Grade 5) was reported. Treatment was discontinued due to an AE in 9 of 45 (20%). CONCLUSIONS:Everolimus, and to a lesser extent sirolimus, are increasingly being used to treat TSC infants and very young children for multiple TSC-associated clinical indications. While AEs were common, most were not severe and did not prevent continued treatment in the majority of this younger population.
Authors: Iris E Overwater; André B Rietman; Agnies M van Eeghen; Marie Claire Y de Wit Journal: Ther Clin Risk Manag Date: 2019-07-26 Impact factor: 2.423
Authors: S Katie Z Ihnen; Jamie K Capal; Paul S Horn; Molly Griffith; Mustafa Sahin; E Martina Bebin; Joyce Y Wu; Hope Northrup; Darcy A Krueger Journal: Pediatr Neurol Date: 2021-07-06 Impact factor: 4.210
Authors: Afshin Saffari; Ines Brösse; Adelheid Wiemer-Kruel; Bernd Wilken; Paula Kreuzaler; Andreas Hahn; Matthias K Bernhard; Cornelis M van Tilburg; Georg F Hoffmann; Matthias Gorenflo; Sven Hethey; Olaf Kaiser; Stefan Kölker; Robert Wagner; Olaf Witt; Andreas Merkenschlager; Andreas Möckel; Timo Roser; Jan-Ulrich Schlump; Antje Serfling; Juliane Spiegler; Till Milde; Andreas Ziegler; Steffen Syrbe Journal: Orphanet J Rare Dis Date: 2019-05-03 Impact factor: 4.123