Pharmacokinetic evaluation of the PNC disassembler metarrestin in wild-type and Pdx1-Cre;LSL-KrasG12D/+;Tp53R172H/+ (KPC) mice, a genetically engineered model of pancreatic cancer

作者：Tomas Vilimas, Amy Q. Wang, Samarjit Patnaik, Emma Hughes, Marc Singleton, Zachary Knotts, Dandan Li, Kevin J. Frankowski, Jerome Schlomer, Theresa M. Guerin, Stephanie K. Springer, Catherine L. Drennan, Christopher Dextras, Chen Wang, Debra J. Gilbert, Noel Southall, Marc Ferrer, Sui Huang, Serguei Kozlov, Juan Marugán, Xin Xu, Udo Rudloff · 发表于：Cancer Chemotherapy and Pharmacology · 年份：2018 · DOI：10.1007/s00280-018-3699-0 · 被引用次数：14 · 研究领域：FOXO transcription factor regulation、Cancer Cells and Metastasis、Cancer Mechanisms and Therapy

Metarrestin is a first-in-class small molecule clinical candidate capable of disrupting the perinucleolar compartment, a subnuclear structure unique to metastatic cancer cells. This study aims to define the pharmacokinetic (PK) profile of metarrestin and the pharmacokinetic/pharmacodynamic relationship of metarrestin-regulated markers. PK studies included the administration of single or multiple dose of metarrestin at 3, 10, or 25 mg/kg via intravenous (IV) injection, gavage (PO) or with chow to wild-type C57BL/6 mice and KPC mice bearing autochthonous pancreatic tumors. Metarrestin concentrations were analyzed by UPLC–MS/MS. Pharmacodynamic assays included mRNA expression profiling by RNA-seq and qRT-PCR for KPC mice. Metarrestin had a moderate plasma clearance of 48 mL/min/kg and a large volume of distribution of 17 L/kg at 3 mg/kg IV in C57BL/6 mice. The oral bioavailability after single-dose (SD) treatment was > 80%. In KPC mice treated with SD 25 mg/kg PO, plasma AUC 0–∞ of 14400 ng h/mL, C max of 810 ng/mL and half-life ( t 1/2 ) of 8.5 h were observed. At 24 h after SD of 25 mg/kg PO, the intratumor concentration of metarrestin was high with a mean value of 6.2 µg/g tissue (or 13 µM), well above the cell-based IC 50 of 0.4 µM. At multiple dose (MD) 25 mg/kg/day PO in KPC mice, mean tissue/plasma AUC 0–24h ratio for tumor, spleen and liver was 37, 30 and 31, respectively. There was a good linear relationship of dosage to AUC 0–24h and C 24h . AUC 0–24h MD to AUC 0–24h S...