Exposure-Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy.

摘要: Exposure-response relationships of vamorolone, a novel dissociative steroidal anti-inflammatory drug, were investigated in clinical trials boys with Duchenne muscular dystrophy. Variables outcome measures, Fridericia-corrected QT (QTcF) duration, and pharmacodynamic (PD) biomarkers. Exposure metrics area under the plasma concentration time curve (AUC) maximum (Cmax ), sigmoid Emax model applied. Significant improvement efficacy outcomes was observed after 24 weeks daily dosing. The primary outcome, to stand from supine velocity, exhibited highest sensitivity lowest AUC value providing 50% effect (E50  = 186 ng·h/mL), followed by climb 4 stairs  = 478 run/walk 10 m  = 1220 6-minute walk test  = 1770 ng·h/mL). Week 2 changes proinflammatory PD biomarkers showed exposure-dependent decreases. E50 260 ng·h/mL for insulin-like growth factor-binding protein 2, 1200 matrix metalloproteinase 12, 1260 lymphotoxin α1/β2, 1340 CD23, 1420 interleukin-22-binding protein, 1600 macrophage-derived chemokine/C-C motif chemokine 22. No relationship found between QTcF interval baseline Cmax week or 24. This analysis that improvements end points achieved at typical vamorolone exposure mg/kg dose median 6 (3651 corresponding approximately 95% effects most response variables.