RT Journal Article SR Electronic T1 The usefulness of determining plasma and tissue concentrations of phosphorodiamidate morpholino oligonucleotides to estimate their efficacy in Duchenne muscular dystrophy patients JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP DMD-AR-2024-001806 DO 10.1124/dmd.124.001806 A1 Imai, Shunji A1 Watanabe, Naoki A1 Tone, Yuichiro A1 Mitamura, Rei A1 Mori, Jumpei A1 Kameyama, Tsubasa A1 Yamada, Tetsuhiro A1 Kusano, Kazutomi YR 2024 UL http://dmd.aspetjournals.org/content/early/2024/07/11/dmd.124.001806.abstract AB Currently four kinds of phosphorodiamidate morpholino oligomers (PMOs) such as viltolarsen have been approved for the treatment of Duchenne muscular dystrophy (DMD); however, it is unclear whether human efficacy can be estimated using plasma concentrations. This study summarizes the tissue distribution of viltolarsen in mice and cynomolgus monkeys and evaluates the relationship between exposure and efficacy based on exon skipping. In the tissue distribution studies, all muscles in DMD model mice showed higher concentrations of viltolarsen than those in wild-type mice and cynomolgus monkeys, and the concentrations in skeletal muscle were correlated with the exon-skipping efficiency in mice and cynomolgus monkeys. In addition, a highly sensitive bioanalytical method using liquid chromatography with tandem mass spectrometry shows promise for determining plasma concentrations up to a later time point, and the tissue (muscle)/plasma concentration ratio (Kp) in DMD model mice was shown to be useful for predicting changes in pharmacodynamic (PD) markers in humans. Our results suggest that pharmacokinetic (PK)/PD analysis can be conducted by using the human PK profile or Kp values and skipping efficiency in DMD model mice. This information will be useful for the efficient and effective development of PMOs as therapeutic agents. Significance Statement We compare that plasma and tissue concentrations with the efficiency of exon skipping for viltolarsen as an example phosphorodiamidate morpholino oligomers in skeletal and cardiac muscle of mice and cynomolgus monkeys for pharmacokinetics/pharmacodynamics (PK/PD) analysis. Our results suggest that PK/PD analysis can be conducted by using the human PK profile or Kp values and skipping efficiency in DMD model mice.