Preclinical and Clinical Pharmacokinetics of JNJ‐75220795, an siRNA Therapeutic Targeting PNPLA3 , for Metabolic Dysfunction‐Associated Steatohepatitis

作者：Jae Yoon Jeon, Vivaswath S. Ayyar, Shohei Ouchi, Elisa Fabbrini, Anastasiya Koshkina, Jeffery J. Prusakiewicz, Jed Dallas, Txheng Yang, Wenying Jian, Lijuan Kang, Korin Cofsky, Brian Rady, Ryo Tamamura, Yuki Saito, Aimi Yamashita, Tamisha Vaughan, Susan Wendel, Hideo Makimura, Dénes Csonka, Navin Goyal · 发表于：The Journal of Clinical Pharmacology · 年份：2024 · DOI：10.1002/jcph.6174 · 被引用次数：6 · 研究领域：Liver Disease Diagnosis and Treatment、Endoplasmic Reticulum Stress and Disease、Pancreatitis Pathology and Treatment

Abstract JNJ‐75220795 or ARO‐PNPLA3 is an investigational small interfering ribonucleic acid agent conjugated with N‐acetyl‐ d ‐galactosamine that targets the PNPLA3 gene, currently being developed for metabolic dysfunction‐associated steatohepatitis (MASH). This study evaluated the pharmacokinetics (PK) profile of single subcutaneous doses of JNJ‐75220795 in preclinical species as well as in human subjects with homozygous or heterozygous PNPLA3 I148M mutation in two phase 1 studies—a first‐in‐human study in the United States and a first‐in‐Japanese study in Japan. Preclinical PK in rats and non‐human primates (NHP) showed a rapid systemic absorption and elimination following single subcutaneous doses. JNJ‐75220795 was predominantly distributed to the liver with peak liver concentrations reached at 4 h and still detectable at 672 and 336 h in rats and NHPs, respectively, with an apparent liver‐to‐plasma area under the curve (AUC) ratio of 2800 in rats. Consistent with the preclinical findings, clinical PK showed rapid systemic absorption and clearance in humans with median peak concentrations at 3.0‐9.0 h and mean short half‐life of 3.4‐6.2 h. Plasma PK exposure parameters including C max and AUC increased approximately dose proportionally. Kidney had the second highest tissue exposure following the liver in rats. Renal excretion was a significant but minor elimination pathway as approximately 15%‐25% of the administered dose was recovered in urine. Based on the overall data,...