Five multivariate Duchenne muscular dystrophy progression models bridging six-minute walk distance and MRI relaxometry of leg muscles

the DMD MR Biomarker Steering Committee

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The study aimed to provide quantitative information on the utilization of MRI transverse relaxation time constant (MRI-T2) of leg muscles in DMD clinical trials by developing multivariate disease progression models of Duchenne muscular dystrophy (DMD) using 6-min walk distance (6MWD) and MRI-T2. Clinical data were collected from the prospective and longitudinal ImagingNMD study. Disease progression models were developed by a nonlinear mixed-effect modeling approach. Univariate models of 6MWD and MRI-T2 of five muscles were developed separately. Age at assessment was the time metric. Multivariate models were developed by estimating the correlation of 6MWD and MRI-T2 model variables. Full model estimation approach for covariate analysis and five-fold cross validation were conducted. Simulations were performed to compare the models and predict the covariate effects on the trajectories of 6MWD and MRI-T2. Sigmoid Imax and Emax models best captured the profiles of 6MWD and MRI-T2 over age. Steroid use, baseline 6MWD, and baseline MRI-T2 were significant covariates. The median age at which 6MWD is half of its maximum decrease in the five models was similar, while the median age at which MRI-T2 is half of its maximum increase varied depending on the type of muscle. The models connecting 6MWD and MRI-T2 successfully quantified how individual characteristics alter disease trajectories. The models demonstrate a plausible correlation between 6MWD and MRI-T2, supporting the use of MRI-T2. The developed models will guide drug developers in using the MRI-T2 to most efficient use in DMD clinical trials.

Original languageEnglish (US)
Pages (from-to)671-683
Number of pages13
JournalJournal of Pharmacokinetics and Pharmacodynamics
Volume51
Issue number6
DOIs
StatePublished - Dec 2024

Keywords

  • Clinical trial simulation
  • Disease progression
  • Drug development tools
  • Duchenne muscular dystrophy
  • Magnetic resonance imaging
  • Model-informed drug development
  • Quantitative imaging biomarkers
  • Rare diseases
  • Six-minute walk distance

ASJC Scopus subject areas

  • Pharmacology

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