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dc.contributor.authorVilimas, Tomas
dc.contributor.authorWang, Amy Q.
dc.contributor.authorPatnaik, Samarjit
dc.contributor.authorHughes, Emma A.
dc.contributor.authorSingleton, Marc D.
dc.contributor.authorKnotts, Zachary
dc.contributor.authorLi, Dandan
dc.contributor.authorFrankowski, Kevin
dc.contributor.authorSchlomer, Jerome J.
dc.contributor.authorGuerin, Theresa M.
dc.contributor.authorSpringer, Stephanie
dc.contributor.authorDrennan, Catherine
dc.contributor.authorDextras, Christopher
dc.contributor.authorWang, Chen
dc.contributor.authorGilbert, Debra
dc.contributor.authorSouthall, Noel
dc.contributor.authorFerrer, Marc
dc.contributor.authorHuang, Sui
dc.contributor.authorKozlov, Serguei
dc.contributor.authorMarugan, Juan
dc.contributor.authorXu, Xin
dc.contributor.authorRudloff, Udo
dc.identifier.citationVilimas, T., Wang, A. Q., Patnaik, S., Hughes, E. A., Singleton, M. D., Knotts, Z., Li, D., Frankowski, K., Schlomer, J. J., Guerin, T. M., Springer, S., Drennan, C., Dextras, C., Wang, C., Gilbert, D., Southall, N., Ferrer, M., Huang, S., Kozlov, S., Marugan, J., … Rudloff, U. (2018). 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. Cancer chemotherapy and pharmacology, 82(6), 1067–1080.
dc.descriptionThis work is licensed under a Creative Commons Attribution 4.0 International License.en_US
dc.description.abstractPurpose 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.

Methods 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.

Results 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 AUC0–∞ of 14400 ng h/mL, Cmax of 810 ng/mL and half-life (t1/2) 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 IC50 of 0.4 µM. At multiple dose (MD) 25 mg/kg/day PO in KPC mice, mean tissue/plasma AUC0–24h ratio for tumor, spleen and liver was 37, 30 and 31, respectively. There was a good linear relationship of dosage to AUC0–24h and C24h. AUC0–24h MD to AUC0–24h SD ratios ranged from two for liver to five for tumor indicating additional accumulation in tumors. Dose-dependent normalization of FOXA1 and FOXO6 mRNA expression was observed in KPC tumors.

Conclusions Metarrestin is an effective therapeutic candidate with a favorable PK profile achieving excellent intratumor tissue levels in a disease with known poor drug delivery.
dc.description.sponsorshipIntramural Research Program (IRP) of the NIHen_US
dc.description.sponsorshipNational Cancer Instituteen_US
dc.description.sponsorshipCenter for Cancer Research (ZIA BC 011267)en_US
dc.rights© The Author(s) 2018en_US
dc.subjectPeri-nucleolar compartment (PNC)en_US
dc.subjectKPC miceen_US
dc.titlePharmacokinetic evaluation of the PNC disassembler metarrestin in wild-type and Pdx1-Cre;LSL-KrasG12D/+;Tp53R172H/+ (KPC) mice, a genetically engineered model of pancreatic canceren_US
kusw.kuauthorFrankowski, Kevin
kusw.kudepartmentMedicinal Chemistryen_US
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US

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