Population Pharmacokinetics of Vamorolone (VBP15) in Healthy Men and Boys With Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder occurring in boys and caused by mutations in the dystrophin gene. Vamorolone is a first-generation delta-9,11 compound that has favorable efficacy and side effect profiles relative to classical glucocorticoids. The pharmacokinetics (PK) of oral vamorolone were assessed in parallel-group studies in healthy men (phase 1, n = 86) and boys with DMD (phase 2a, n = 48) during 14 days of once-daily dosing with a range of doses. Vamorolone exhibited moderate variability in PK, with the maximum plasma concentration usually occurring at 2-4 hours and a half-life of approximately 2 hours for all doses and days examined. Population PK modeling of all data together indicated that the PK of vamorolone can be well described by a 1-compartment model with zero-order absorption. Both men and boys showed a dose-linearity of PK parameters for the doses examined, with no accumulation of the drug during daily dosing. Ingestion with food resulted in markedly enhanced absorption of the drug, as tested in healthy men. There were similar PK of vamorolone in healthy men and DMD boys with apparent clearance averaging 2.0 L/h/kg in men and 1.7 L/h/kg in boys. Overall, vamorolone exhibited well-behaved linear PK, with similar profiles in healthy men and boys with DMD, moderate variability in PK parameters, and absorption and disposition profiles similar to those of classical glucocorticoids.

Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study

“…The first multiple ascending dose (MAD) cohort trial tested pharmacokinetics (PK) and safety for 2 weeks of drug dosing followed by a 2-week washout (VBP15-002) [11]. Vamorolone treatment in this study showed no dose-limiting toxicities, and PK demonstrated a short half-life similar to corticosteroids (~2 hours), no drug accumulation, similar PK on day 1 and day 14, and PK similar to that of healthy adult male volunteers (VBP15-001) [9,[11][12][13]. All DMD participants completed the MAD study and then continued on the same dose for a 24-week dosefinding (efficacy and safety) extension study (VBP15-003).…”

“…VBP15-003 was a 24-week dose-ranging study, with each group (y-axis) of 12 participants started at a specific dose (doses indicated by colors and legend; 0.25 mg/kg/day, 0.75 mg/kg/day, 2.0 mg/kg/ day, 6.0 mg/kg/day). VBP15-LTE is a 2-year long-term extension study, but data presented here are from the midpoint (12…”

Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function

“…Vamorolone showed pharmacokinetics and metabolism similar to those of corticosteroids and is similarly administered with daily oral dosing. 20 The 48 patients with DMD enrolled in the 4 week phase 2a study (VBP15-002) were then enrolled in a 24-week extension study (VBP15-003) to test for drug efficacy, and the latter study is reported here.…”

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

“…Single-and multipledose pharmacokinetics (PK) of oral vamorolone in both healthy male volunteers and DMD boys (Table 1) were assessed previously based on noncompartmental analysis and population PK modeling. 19 Overall, vamorolone exhibited moderate variability in PK, with maximum plasma concentration (C max ) usually occurring at 2-4 hours and a half-life of approximately 2-3 hours for all the doses and days tested. The PK of vamorolone is linear within the dose range studied in both healthy men (0.1-20.0 mg/kg/day) and DMD boys (0.25∼6.0 mg/kg/day), with no evidence of accumulation after multiple daily doses.…”

“…Similar PK was observed in healthy men and boys with DMD, with apparent clearance averaging 2.0 L/h/kg in men and 1.9 L/h/kg in boys. 19 Given the linear and stationary PK properties of vamorolone in DMD boys, the observed area under the curve (AUC) and the C max values on day 14 were used, if available. Otherwise, corresponding values on day 1 were used as the PK exposure for the present E-R analysis ( Table 2).…”