PMID- 37534782 OWN - NLM STAT- MEDLINE DCOM- 20231023 LR - 20240417 IS - 2163-8306 (Electronic) IS - 2163-8306 (Linking) VI - 12 IP - 10 DP - 2023 Oct TI - Multivariate modeling of magnetic resonance biomarkers and clinical outcome measures for Duchenne muscular dystrophy clinical trials. PG - 1437-1449 LID - 10.1002/psp4.13021 [doi] AB - Although regulatory agencies encourage inclusion of imaging biomarkers in clinical trials for Duchenne muscular dystrophy (DMD), industry receives minimal guidance on how to use these biomarkers most beneficially in trials. This study aims to identify the optimal use of muscle fat fraction biomarkers in DMD clinical trials through a quantitative disease-drug-trial modeling and simulation approach. We simultaneously developed two multivariate models quantifying the longitudinal associations between 6-minute walk distance (6MWD) and fat fraction measures from vastus lateralis and soleus muscles. We leveraged the longitudinal individual-level data collected for 10 years through the ImagingDMD study. Age of the individuals at assessment was chosen as the time metric. After the longitudinal dynamic of each measure was modeled separately, the selected univariate models were combined using correlation parameters. Covariates, including baseline scores of the measures and steroid use, were assessed using the full model approach. The nonlinear mixed-effects modeling was performed in Monolix. The final models showed reasonable precision of the parameter estimates. Simulation-based diagnostics and fivefold cross-validation further showed the model's adequacy. The multivariate models will guide drug developers on using fat fraction assessment most efficiently using available data, including the widely used 6MWD. The models will provide valuable information about how individual characteristics alter disease trajectories. We will extend the multivariate models to incorporate trial design parameters and hypothetical drug effects to inform better clinical trial designs through simulation, which will facilitate the design of clinical trials that are both more inclusive and more conclusive using fat fraction biomarkers. CI - (c) 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. FAU - Kim, Sarah AU - Kim S AUID- ORCID: 0000-0002-9179-0735 AD - Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA. FAU - Willcocks, Rebecca J AU - Willcocks RJ AD - Department of Physical Therapy, University of Florida, Gainesville, Florida, USA. FAU - Daniels, Michael J AU - Daniels MJ AD - Department of Statistics, University of Florida, Gainesville, Florida, USA. FAU - Morales, Juan Francisco AU - Morales JF AD - Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA. FAU - Yoon, Deok Yong AU - Yoon DY AD - Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA. FAU - Triplett, William T AU - Triplett WT AD - Department of Physical Therapy, University of Florida, Gainesville, Florida, USA. FAU - Barnard, Alison M AU - Barnard AM AD - Department of Physical Therapy, University of Florida, Gainesville, Florida, USA. FAU - Conrado, Daniela J AU - Conrado DJ AD - e-Quantify LLC, La Jolla, California, USA. FAU - Aggarwal, Varun AU - Aggarwal V AUID- ORCID: 0000-0002-8406-0961 AD - Critical Path Institute, Tucson, Arizona, USA. FAU - Belfiore-Oshan, Ramona AU - Belfiore-Oshan R AD - Critical Path Institute, Tucson, Arizona, USA. FAU - Martinez, Terina N AU - Martinez TN AD - Critical Path Institute, Tucson, Arizona, USA. FAU - Walter, Glenn A AU - Walter GA AD - Department of Physiology and Aging, University of Florida, Gainesville, Florida, USA. FAU - Rooney, William D AU - Rooney WD AD - Advanced Imaging Research Center, Oregon Health & Science University, Portland, Oregon, USA. FAU - Vandenborne, Krista AU - Vandenborne K AD - Department of Physical Therapy, University of Florida, Gainesville, Florida, USA. LA - eng GR - S10 OD018224/OD/NIH HHS/United States GR - R01 HL158963/HL/NHLBI NIH HHS/United States GR - UL1 TR002369/TR/NCATS NIH HHS/United States GR - UL1 TR001427/TR/NCATS NIH HHS/United States GR - R01 AR056973/AR/NIAMS NIH HHS/United States GR - S10 OD021701/OD/NIH HHS/United States GR - K12 HD055929/HD/NICHD NIH HHS/United States GR - R21 TR004006/TR/NCATS NIH HHS/United States PT - Journal Article DEP - 20230827 PL - United States TA - CPT Pharmacometrics Syst Pharmacol JT - CPT: pharmacometrics & systems pharmacology JID - 101580011 RN - 0 (Biomarkers) SB - IM MH - Humans MH - *Muscular Dystrophy, Duchenne/drug therapy MH - Magnetic Resonance Spectroscopy/methods MH - Magnetic Resonance Imaging/methods MH - Biomarkers MH - Outcome Assessment, Health Care PMC - PMC10583249 COIS- The authors declared no competing interests for this work. EDAT- 2023/08/03 13:08 MHDA- 2023/10/23 12:43 PMCR- 2023/08/27 CRDT- 2023/08/03 08:03 PHST- 2023/07/08 00:00 [revised] PHST- 2023/03/17 00:00 [received] PHST- 2023/07/24 00:00 [accepted] PHST- 2023/10/23 12:43 [medline] PHST- 2023/08/03 13:08 [pubmed] PHST- 2023/08/03 08:03 [entrez] PHST- 2023/08/27 00:00 [pmc-release] AID - PSP413021 [pii] AID - 10.1002/psp4.13021 [doi] PST - ppublish SO - CPT Pharmacometrics Syst Pharmacol. 2023 Oct;12(10):1437-1449. doi: 10.1002/psp4.13021. Epub 2023 Aug 27.