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

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.

Keywords: Kawasaki disease; atorvastatin; coronary artery abnormalities; statin.

Copyright © 2019 Elsevier Inc. All rights reserved.

Figures

Figure 1 online.

Participant CONSORT flow diagram. Of the 37 subjects assessed for eligibility, one did not meet inclusion criteria (had a chronic underlying disorder that excluded participation), one declined (concerned about risks of atorvastatin) and one discontinued atorvastatin upon discharge home.

Figure 2.

Levels of 24(S)-hydroxycholesterol with and without atorvastatin therapy and across dose levels. (A) 24(S)-hydroxycholesterol levels after 6 weeks of KD diagnosis is shown in KD subjects who received IVIG and infliximab versus IVIG, infliximab and atorvastatin. (B) The individual 24(S) hydroxycholesterol level for each KD subject treated with atorvastatin is shown by dose level. Red: 0.25 mg/kg, Green: 0.5 mg/kg, Purple: 0.75 mg/kg, Black: without atorvastatin treatment.

Figure 3.

Median concentration of (A) atorvastatin and (B) ortho-hydroxyatorvastatin metabolite versus time by dose in mg/kg. Increasing doses of atorvastatin and its active metabolite, ortho-hydroxyatorvastatin, are shown. Blue, 0.125 mg/kg/day; red, 0.25 mg/kg/day; green 0.5 mg/kg/day; purple 0.75 mg/kg/day.

Figure 4 online:

Plasma protein carbonyl concentration. A) The plasma protein carbonyl concentration (median and IQR) is are shown for samples acquired prior to IVIG administration (baseline) and after two weeks of atorvastatin compared with samples from matched KD control (ctl) patients B) The difference in plasma protein carbonyl concentration (baseline minus 2 week) for study subjects and matched control KD patients (median and IQR).

Figure 5 online:

Z-score over course of treatment with atorvastatin. (A) Left anterior descending (LAD) coronary artery Z score at baseline (pre-IVIG) and 2 and 6 weeks after treatment with atorvastatin. (B) Right coronary artery (RCA) Z score pre-IVIG and 2 and 6 weeks after treatment with atorvastatin. Blue, 0.125 mg/kg/day; red, 0.25 mg/kg/day; green 0.5 mg/kg/day; purple 0.75 mg/kg/day.

Figure 6 online:

Immunophenotyping of peripheral blood mononuclear cells in patients with Kawasaki disease treated with IVIG, infliximab, and atorvastatin or IVIG and infliximab only. Subjects 1, 2, 4 and 5 received 0.75 mg/kg/day of atorvastatin and subject 3 received 0.5 mg/kg/day. Panels A and B: Characterization of myeloid dendritic cells (mDC) by flow cytometry: CD11c+ CD11b+ mDC (dot plots) were gated on CD14− and CD14+ populations (histograms) and evaluated for CD86 expression to determine their maturation/activation stage. Panels C and D: Characterization of T cell lineages by flow cytometry: CD4+ and CD8+ T cells were enumerated and evaluated for their activation/expansion by measuring DR and IL-7R expression. Regulatory T cells (Treg) were enumerated by gating on CD4+ CD25high cells (dot plots) and evaluated for IL-7R and CD45RA expression that define peripherally induced Treg (iTreg). Natural Treg that mature in the thymus (nTreg) are IL-7R – and CD45RA−. DR expression on iTreg and nTreg defines their activation stage.

Figure 6 online:

Immunophenotyping of peripheral blood mononuclear cells in patients with Kawasaki disease treated with IVIG, infliximab, and atorvastatin or IVIG and infliximab only. Subjects 1, 2, 4 and 5 received 0.75 mg/kg/day of atorvastatin and subject 3 received 0.5 mg/kg/day. Panels A and B: Characterization of myeloid dendritic cells (mDC) by flow cytometry: CD11c+ CD11b+ mDC (dot plots) were gated on CD14− and CD14+ populations (histograms) and evaluated for CD86 expression to determine their maturation/activation stage. Panels C and D: Characterization of T cell lineages by flow cytometry: CD4+ and CD8+ T cells were enumerated and evaluated for their activation/expansion by measuring DR and IL-7R expression. Regulatory T cells (Treg) were enumerated by gating on CD4+ CD25high cells (dot plots) and evaluated for IL-7R and CD45RA expression that define peripherally induced Treg (iTreg). Natural Treg that mature in the thymus (nTreg) are IL-7R – and CD45RA−. DR expression on iTreg and nTreg defines their activation stage.

Figure 6 online:

Immunophenotyping of peripheral blood mononuclear cells in patients with Kawasaki disease treated with IVIG, infliximab, and atorvastatin or IVIG and infliximab only. Subjects 1, 2, 4 and 5 received 0.75 mg/kg/day of atorvastatin and subject 3 received 0.5 mg/kg/day. Panels A and B: Characterization of myeloid dendritic cells (mDC) by flow cytometry: CD11c+ CD11b+ mDC (dot plots) were gated on CD14− and CD14+ populations (histograms) and evaluated for CD86 expression to determine their maturation/activation stage. Panels C and D: Characterization of T cell lineages by flow cytometry: CD4+ and CD8+ T cells were enumerated and evaluated for their activation/expansion by measuring DR and IL-7R expression. Regulatory T cells (Treg) were enumerated by gating on CD4+ CD25high cells (dot plots) and evaluated for IL-7R and CD45RA expression that define peripherally induced Treg (iTreg). Natural Treg that mature in the thymus (nTreg) are IL-7R – and CD45RA−. DR expression on iTreg and nTreg defines their activation stage.

Figure 6 online:

Immunophenotyping of peripheral blood mononuclear cells in patients with Kawasaki disease treated with IVIG, infliximab, and atorvastatin or IVIG and infliximab only. Subjects 1, 2, 4 and 5 received 0.75 mg/kg/day of atorvastatin and subject 3 received 0.5 mg/kg/day. Panels A and B: Characterization of myeloid dendritic cells (mDC) by flow cytometry: CD11c+ CD11b+ mDC (dot plots) were gated on CD14− and CD14+ populations (histograms) and evaluated for CD86 expression to determine their maturation/activation stage. Panels C and D: Characterization of T cell lineages by flow cytometry: CD4+ and CD8+ T cells were enumerated and evaluated for their activation/expansion by measuring DR and IL-7R expression. Regulatory T cells (Treg) were enumerated by gating on CD4+ CD25high cells (dot plots) and evaluated for IL-7R and CD45RA expression that define peripherally induced Treg (iTreg). Natural Treg that mature in the thymus (nTreg) are IL-7R – and CD45RA−. DR expression on iTreg and nTreg defines their activation stage.

Figure 7 online.

Percentage of circulating CD4+ and CD8+ T cells, including activated (HLA-DR+) T cells for KD patients treated with (statin +) and without (statin −) atorvastatin.