Jincheng Yang1, Sonia Jain2, Edmund V Capparelli1, Brookie M Best1, Mary Beth Son3, Annette Baker4, Jane W Newburger5, Alessandra Franco6, Beth F Printz7, Feng He2, Chisato Shimizu6, Shinsuke Hoshino6, Emelia Bainto6, Elizabeth Moreno6, Joan Pancheri6, Jane C Burns6, Adriana H Tremoulet8. 1. Kawasaki Disease Research Center, Department of Pediatrics, University of California San Diego and Rady Children's Hospital, San Diego, CA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA. 2. Biostatistics Research Center, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA. 3. Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Boston, MA. 4. Department of Cardiology, Boston Children's Hospital, Boston, MA. 5. Department of Cardiology, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA. 6. Kawasaki Disease Research Center, Department of Pediatrics, University of California San Diego and Rady Children's Hospital, San Diego, CA. 7. Division of Pediatric Cardiology, Department of Pediatrics, University of California San Diego and Rady Children's Hospital, San Diego, CA. 8. Kawasaki Disease Research Center, Department of Pediatrics, University of California San Diego and Rady Children's Hospital, San Diego, CA. Electronic address: atremoulet@health.ucsd.edu.
Abstract
OBJECTIVES: To determine the safety, pharmacokinetics, and immunomodulatory effects of 2-6 weeks of anakinra therapy in patients with acute Kawasaki disease with a coronary artery aneurysm (CAA). STUDY DESIGN: We performed a Phase I/IIa dose-escalation study of anakinra (2-11 mg/kg/day) in 22 patients with acute Kawasaki disease with CAA. We measured interleukin (IL)-1RA concentrations after the first dose and trough levels up to study week 6. Markers of inflammation and coronary artery z-scores were assessed pretreatment and at 48 hours, 2 weeks, and 6 weeks after initiation of therapy. RESULTS: Up to 6 weeks of anakinra (up to 11 mg/kg/day) was safe and well tolerated by the 22 participants (median age, 1.1 years), with no serious adverse events attributable to the study drug. All participants were treated with intravenous immunoglobulin (IVIG), and 20 also received infliximab (10 mg/kg) before initiation of anakinra. Serum levels of IL-6, IL-8, and tumor necrosis factor α decreased similarly in patients with Kawasaki disease treated with IVIG, infliximab, and anakinra compared with age- and sex-matched patients with Kawasaki disease treated only with IVIG and infliximab. Anakinra clearance increased with illness day at diagnosis. Simulations demonstrated that more frequent intravenous (IV) dosing may result in more sustained concentrations without significantly increasing the peak concentration compared with subcutaneous (SC) dosing. CONCLUSIONS: Both IV and SC anakinra are safe in infants and children with acute Kawasaki disease and CAA. IV dosing every 8-12 hours during the acute hospitalization of patients with Kawasaki disease may result in a sustained concentration while avoiding frequent SC injections. The efficacy of a short course of IV therapy during hospitalization should be studied. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT02179853.
OBJECTIVES: To determine the safety, pharmacokinetics, and immunomodulatory effects of 2-6 weeks of anakinra therapy in patients with acute Kawasaki disease with a coronary artery aneurysm (CAA). STUDY DESIGN: We performed a Phase I/IIa dose-escalation study of anakinra (2-11 mg/kg/day) in 22 patients with acute Kawasaki disease with CAA. We measured interleukin (IL)-1RA concentrations after the first dose and trough levels up to study week 6. Markers of inflammation and coronary artery z-scores were assessed pretreatment and at 48 hours, 2 weeks, and 6 weeks after initiation of therapy. RESULTS: Up to 6 weeks of anakinra (up to 11 mg/kg/day) was safe and well tolerated by the 22 participants (median age, 1.1 years), with no serious adverse events attributable to the study drug. All participants were treated with intravenous immunoglobulin (IVIG), and 20 also received infliximab (10 mg/kg) before initiation of anakinra. Serum levels of IL-6, IL-8, and tumor necrosis factor α decreased similarly in patients with Kawasaki disease treated with IVIG, infliximab, and anakinra compared with age- and sex-matched patients with Kawasaki disease treated only with IVIG and infliximab. Anakinra clearance increased with illness day at diagnosis. Simulations demonstrated that more frequent intravenous (IV) dosing may result in more sustained concentrations without significantly increasing the peak concentration compared with subcutaneous (SC) dosing. CONCLUSIONS: Both IV and SC anakinra are safe in infants and children with acute Kawasaki disease and CAA. IV dosing every 8-12 hours during the acute hospitalization of patients with Kawasaki disease may result in a sustained concentration while avoiding frequent SC injections. The efficacy of a short course of IV therapy during hospitalization should be studied. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT02179853.
Authors: Caroline Diorio; Anant Vatsayan; Aimee C Talleur; Colleen Annesley; Jennifer J Jaroscak; Haneen Shalabi; Amanda K Ombrello; Michelle Hudspeth; Shannon L Maude; Rebecca A Gardner; Nirali N Shah Journal: Blood Adv Date: 2022-06-14