43 - A PHASE I/IIA TRIAL OF ATROVASTATIN IN JAPANESE PATIENTS WITH ACUTE KAWASAKI DISEASE AND CORONARY ARTERY ANEURYSMS: A MULTICENTER, SINGLE-ARM, OPEN-LABEL TRIAL

Backgraund

In the United States, a phase I/IIa dose-escalation study of atorvastatin in KD patients with CAAs demonstrated the safety and pharmacokinetics (PK) of atorvastatin. However, due to the variability of atorvastatin metabolism in the Asian population, we examined the tolerability and PK of atorvastatin in Japanese children with acute KD and CAAs.

Methods

This multicenter, single-arm, open-label, phase I/IIa study of atorvastatin in acute KD patients with CAAs in Japan recruited patients for a 3+3 dose-escalation study of a 6-week course of atorvastatin (0.125 to 0.5 mg/kg/day). The primary outcome was the safety of atorvastatin. The secondary outcomes were the PK of atorvastatin, biomarkers of inflammation, and echocardiographic assessment of CAAs.

Results

We enrolled nine KD patients in this study. No dose-limiting toxicity was observed. Therefore, we determined the maximum tolerated dose in this study was 0.5 mg/kg/day. Although there were no serious adverse drug reactions, two participants showed minor elevations in alanine or aspartate aminotransferase that recovered spontaneously without discontinuation of atorvastatin. No patient experienced an elevation in serum CK levels. The Z-scores of each coronary artery in all participants decreased from baseline to the 6-week visit except for one lesion. The estimated median Cmax at the 0.125 mg/kg, 0.25 mg/kg, and 0.5 mg/kg doses were 5.31, 14.2, and 33.3 ng/mL, respectively. The estimated median trough (C24) was 0.59, 1.06, and 1.86 ng/mL, respectively. These were similar to those reported in PK studies of atorvastatin conducted in children with KD in the US between the ages of 2 and 17 years. No significant differences in estimated PK parameters were observed in each dose group compared to previous studies.

Conclusions

We found that atorvastatin was safe and a dose up to 0.5 mg/kg/day for 6 weeks was well tolerated in Japanese children with acute KD and CAAs. The PK parameters of atorvastatin were similar to those in non-Japanese children. Further large-scale, prospective studies are warranted to assess the efficacy of atorvastatin in preventing the formation or progression of CAAs.

Trial registry number: Japanese Registry of Clinical Trials (ACTRN12613000112763, December 19, 2018)