Phase I/IIa Trial of Atorvastatin in Patients with Acute Kawasaki Disease with Coronary Artery Aneurysm.

Marsha S Anderson, Jane C Burns, John C Whitin, Harvey J Cohen, Joan Pancheri, Emelia Bainto, Chisato Shimizu, Robert L Padilla, Feng He, Mary P Glodé, Adriana H Tremoulet, Heather Heizer, Samuel R Dominguez, Beth Printz, Alessandra Franco, Elizabeth H Duxbury, Brookie M Best, Pei-Ni Jone, Sonia Jain

Journal: The Journal of pediatrics 2020;215():107-117.e12

PMID: 31561960

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Abstract

OBJECTIVES

To determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of a 6-week course of atorvastatin in patients with acute Kawasaki disease with coronary artery (CA) aneurysm (CAA).

STUDY DESIGN

This was a Phase I/IIa 2-center dose-escalation study of atorvastatin (0.125-0.75 mg/kg/day) in 34 patients with Kawasaki disease (aged 2-17 years) with echocardiographic evidence of CAA. We measured levels of the brain metabolite 24(S)-hydroxycholesterol (24-OHC), serum lipids, acute-phase reactants, liver enzymes, and creatine phosphokinase; peripheral blood mononuclear cell populations; and CA internal diameter normalized for body surface area before atorvastatin treatment and at 2 and 6 weeks after initiation of atorvastatin treatment.

RESULTS

A 6-week course of up to 0.75 mg/kg/day of atorvastatin was well tolerated by the 34 subjects (median age, 5.3 years; IQR, 2.6-6.4 years), with no serious adverse events attributable to the study drug. The areas under the curve for atorvastatin and its metabolite were larger in the study subjects compared with those reported in adults, suggesting a slower rate of metabolism in children. The 24-OHC levels were similar between the atorvastatin-treated subjects and matched controls.

CONCLUSIONS

Atorvastatin was safe and well tolerated in our cohort of children with acute Kawasaki disease and CAA. A Phase III efficacy trial is warranted in this patient population, which may benefit from the known anti-inflammatory and immunomodulatory effects of this drug.

Address: Kawasaki Disease Research Center, Department of Pediatrics, University of California San Diego, La Jolla, CA; Rady Children's Hospital-San Diego, San Diego, CA. Electronic address: [email protected].; Biostatistics Research Center, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA.; Pediatric Cardiology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO.; Kawasaki Disease Research Center, Department of Pediatrics, University of California San Diego, La Jolla, CA; Rady Children's Hospital-San Diego, San Diego, CA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA.; Kawasaki Disease Research Center, Department of Pediatrics, University of California San Diego, La Jolla, CA; Rady Children's Hospital-San Diego, San Diego, CA.; Pediatric Infectious Disease, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO.; Department of Pediatrics, Stanford University, Stanford, CA.

DOI: 10.1016/j.jpeds.2019.07.064

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MeSH Terms: Administration, Oral, Adolescent, Atorvastatin, Child, Child, Preschool, Coronary Aneurysm, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Mucocutaneous Lymph Node Syndrome