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

Abstract

Myostatin, a negative regulator of skeletal muscle growth, is a therapeutic target in muscle‐wasting diseases. Domagrozumab, a humanized recombinant monoclonal antibody, binds myostatin and inhibits activity. Domagrozumab was investigated in a phase II trial (NCT02310763) as a potential treatment for boys with Duchenne muscular dystrophy (DMD). Pharmacokinetic/pharmacodynamic (PK/PD) modeling is vital in clinical trial design, particularly for determining dosing regimens in pediatric populations. This analysis sought to establish the PK/PD relationship between free domagrozumab and total myostatin concentrations in pediatric patients with DMD using a prior semimechanistic model developed from a phase I study in healthy adult volunteers (NCT01616277) and following inclusion of phase II data. The refined model was developed using a multiple‐step approach comprising structural, random effects, and covariate model development; assessment of model adequacy (goodness‐of‐fit); and predictive performance. Differences in PKs/PDs between healthy adult volunteers and pediatric patients with DMD were quantitatively accounted for and evaluated by predicting myostatin coverage (the percentage of myostatin bound by domagrozumab). The final model parameter estimates and semimechanistic target‐mediated drug disposition structure sufficiently described both domagrozumab and myostatin concentrations in pediatric patients with DMD, and most population parameters were comparable with the prior model (in healthy adult volunteers). Predicted myostatin coverage for phase II patients with DMD was consistently > 90%. Baseline serum myostatin was ~ 65% lower than in healthy adult volunteers. This study provides insights into the regulation of myostatin in healthy adults and pediatric patients with DMD. http://clinicaltrials.gov identifiers: NCT01616277 and NCT02310763.

Nivolumab and ipilimumab population pharmacokinetics in support of pediatric dose recommendations—Going beyond the body‐size effect

“…It has generally been assumed that age does not have additional effects on the PK of mAbs in pediatric patients aged greater than or equal to 2 years after adjusting for the effect of body size. [2][3][4][5][6][7][8][9][10] In prior pediatric PopPK analyses for mAbs, body weight was the most commonly used covariate. [3][4][5][6][7][8][9][10] We had expected that allometric scaling of body weight would be sufficient to describe PK in pediatric patients aged greater than or equal to 2 years.…”

“…[2][3][4][5][6][7][8][9][10] In prior pediatric PopPK analyses for mAbs, body weight was the most commonly used covariate. [3][4][5][6][7][8][9][10] We had expected that allometric scaling of body weight would be sufficient to describe PK in pediatric patients aged greater than or equal to 2 years. However, predictions in pediatric patients based on the nivolumab initial full model with body-weight effect were unsatisfactory.…”

“…Prior analyses did not systematically evaluate the effect of age and body size, which may explain the discrepancy between our findings and those of previous analyses. [2][3][4][5][6][7][8][9][10] The current study has identified the tumor-typedependent contribution of age-associated differences beyond body-size differences to the PKs of mAbs in pediatric patients. In this analysis, young pediatric (<12 years) and adolescent (12-17 years) patients with STs had agedependent decreases in nivolumab CL, with 40% and 20% lower CL, respectively, relative to adults after adjusting for the effect of body size.…”

“…Historically, the PKs of therapeutic monoclonal antibodies (mAbs) were thought to be primarily affected by body size, and mAb PKs in pediatric patients (aged 2-17 years) were frequently described by PopPK models using an allometric relationship between body size and PK parameters. [3][4][5][6][7][8][9][10] Earlier studies concluded that mAb PKs in pediatric patients (6-17 years) were readily predictable from adult PK after correction for the bodyweight effect. 3,8 Similarly, the 2019 FDA guidance indicated that exposure and clearance (CL) of drugs are generally similar between adolescent and adult patients after accounting for the effect of body size.…”

“…Historically, the PKs of therapeutic monoclonal antibodies (mAbs) were thought to be primarily affected by body size, and mAb PKs in pediatric patients (aged 2–17 years) were frequently described by PopPK models using an allometric relationship between body size and PK parameters 3–10 . Earlier studies concluded that mAb PKs in pediatric patients (6–17 years) were readily predictable from adult PK after correction for the body‐weight effect 3,8 .…”