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Cancer Chemother Pharmacol. 2018 Dec;82(6):1067-1080. doi: 10.1007/s00280-018-3699-0. Epub 2018 Oct 10.

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.

Author information

1
Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD, 21702, USA.
2
Therapeutics for Rare and Neglected Diseases (TRND) Program, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
3
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
4
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, 94158, USA.
5
Biophysics Graduate Group, University of California Berkeley, Berkeley, CA, 94720, USA.
6
Rare Tumor Initiative (RTI), Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Hatfield Center, 10 Center Drive, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
7
Department of Medicinal Chemistry and Specialized Chemistry Center, University of Kansas, Lawrence, KS, USA.
8
Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD, 21702, USA.
9
Department of Cell and Molecular Biology, Northwestern University, Chicago, IL, 60611, USA.
10
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA. maruganj@mail.nih.gov.
11
NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bldg B, Rockville, MD, 20850, USA. maruganj@mail.nih.gov.
12
Therapeutics for Rare and Neglected Diseases (TRND) Program, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA. xin.xu3@nih.gov.
13
Rare Tumor Initiative (RTI), Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Hatfield Center, 10 Center Drive, 9000 Rockville Pike, Bethesda, MD, 20892, USA. rudloffu@mail.nih.gov.

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.

KEYWORDS:

KPC mice; Metarrestin; Peri-nucleolar compartment (PNC); Pharmacodynamics; Pharmacokinetics

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