dc.contributor.author | Vilimas, Tomas | |
dc.contributor.author | Wang, Amy Q. | |
dc.contributor.author | Patnaik, Samarjit | |
dc.contributor.author | Hughes, Emma A. | |
dc.contributor.author | Singleton, Marc D. | |
dc.contributor.author | Knotts, Zachary | |
dc.contributor.author | Li, Dandan | |
dc.contributor.author | Frankowski, Kevin | |
dc.contributor.author | Schlomer, Jerome J. | |
dc.contributor.author | Guerin, Theresa M. | |
dc.contributor.author | Springer, Stephanie | |
dc.contributor.author | Drennan, Catherine | |
dc.contributor.author | Dextras, Christopher | |
dc.contributor.author | Wang, Chen | |
dc.contributor.author | Gilbert, Debra | |
dc.contributor.author | Southall, Noel | |
dc.contributor.author | Ferrer, Marc | |
dc.contributor.author | Huang, Sui | |
dc.contributor.author | Kozlov, Serguei | |
dc.contributor.author | Marugan, Juan | |
dc.contributor.author | Xu, Xin | |
dc.contributor.author | Rudloff, Udo | |
dc.date.accessioned | 2020-12-01T15:50:18Z | |
dc.date.available | 2020-12-01T15:50:18Z | |
dc.date.issued | 2018-10-10 | |
dc.identifier.citation | Vilimas, 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. https://doi.org/10.1007/s00280-018-3699-0 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/30937 | |
dc.description | This work is licensed under a Creative Commons Attribution 4.0 International License. | en_US |
dc.description.abstract | Purpose
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. | en_US |
dc.description.sponsorship | Intramural Research Program (IRP) of the NIH | en_US |
dc.description.sponsorship | National Cancer Institute | en_US |
dc.description.sponsorship | Center for Cancer Research (ZIA BC 011267) | en_US |
dc.publisher | Springer | en_US |
dc.rights | © The Author(s) 2018 | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Metarrestin | en_US |
dc.subject | Peri-nucleolar compartment (PNC) | en_US |
dc.subject | KPC mice | en_US |
dc.subject | Pharmacokinetics | en_US |
dc.subject | Pharmacodynamics | en_US |
dc.title | 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 | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Frankowski, Kevin | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.1007/s00280-018-3699-0 | en_US |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC6267684 | en_US |
dc.rights.accessrights | openAccess | en_US |