Population PK and PD Analysis of Domagrozumab in Pediatric Patients with Duchenne Muscular Dystrophy

Figure 1. Distribution density of empirical Bayes estimates (EBE) for baseline and internalization/degradation rate constants parameters. (a) Distribution density for EBEs on baseline. Red and blue lines are the distribution densities of individual random effects for baseline for healthy adult volunteers and pediatric patients with DMD, respectively. (b) Distribution density EBE on internalization/degradation rate constants. Red and blue lines are the distribution densities of individual random effects on internalization/degradation rate constants (kdeg − kint) for healthy adult volunteers and pediatric patients with DMD, respectively. DMD, Duchenne muscular dystrophy.

Figure 2. Evaluation of empirical Bayes estimates (EBEs) on domagrozumab clearance vs (a) age (years) and (b) total body weight (kg) for the final model and model with allometric scaling. Circles are the EBEs for clearance vs. age (a) and body weight (b) for the final model (left) and a model with allometric scaling (right). Blue circles represent pediatric patients with DMD from the phase II study and red circles represent the healthy adult volunteers from the phase I study. Black solid lines and shaded areas are the linear regression and 95% confidence interval, respectively, for the relationship of EBEs vs. covariate values. DMD, Duchenne muscular dystrophy.

Figure 3. Final TMDD model visual predictive check for free domagrozumab concentrations in pediatric patients with DMD. Visual predictive checks are presented for time after first dose (a) and time after dose (b). Observed data are represented by blue circles and the black lines (median (solid), 5th and 95th percentiles (dashed)). The simulated free domagrozumab concentrations for phase II patients with DMD are represented by the red line and red shaded ribbon (median and 95% prediction intervals (PIs) of the median, respectively), and the blue lines and blue shaded ribbons (median and 95% PIs of the 5th and 95th percentiles, respectively). Yellow indicators are the times where observed and simulated data are binned for summaries. DMD, Duchenne muscular dystrophy; TMDD, target‐mediated drug disposition.

Figure 4. Final TMDD model visual predictive check for total myostatin in pediatric patients with DMD. Visual predictive checks are presented for time after first dose (a) and time after dose (b). Observed data are represented by blue circles and the black lines (median (solid), 5th and 95th percentiles (dashed)). The simulated total myostatin concentrations for phase II patients with DMD are represented by the red line and red shaded ribbon (median and 95% prediction intervals (PIs) of the median, respectively), and the blue lines and blue shaded ribbons (median and 95% PIs of the 5th and 95th percentiles, respectively). Yellow indicators are the times where observed and simulated data are binned for summaries. DMD, Duchenne muscular dystrophy; TMDD, target‐mediated drug disposition.

Figure 5. Simulated myostatin coverage. (a) The predicted myostatin coverage following 4 doses of each of 5 mg/kg, 20 mg/kg, and 40 mg/kg every 28 days were simulated using the prior model for pediatric patients with DMD (green), the final model for healthy adult volunteers (blue), and the final model for pediatric patients with DMD (red). Lines represent the median, and ribbons depict the 95% prediction intervals (PIs) for a population of 500 subjects. (b) The predicted myostatin coverage following the administration of 0, 1, 2, 3, 5, 7, 10, 20, 30, 40, 60, and 80 mg/kg of domagrozumab every 4 weeks for 48 weeks using the final model for 500 pediatric patients with DMD. Lines represent the median, and ribbons depict the 95% prediction intervals. DMD, Duchenne muscular dystrophy.