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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

Vilimas, Tomas
Wang, Amy Q.
Patnaik, Samarjit
Hughes, Emma A.
Singleton, Marc D.
Knotts, Zachary
Li, Dandan
Frankowski, Kevin
Schlomer, Jerome J.
Guerin, Theresa M.
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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.
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This work is licensed under a Creative Commons Attribution 4.0 International License.
Date
2018-10-10
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Springer
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Keywords
Metarrestin, Peri-nucleolar compartment (PNC), KPC mice, Pharmacokinetics, Pharmacodynamics
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
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