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

Autor: Juan J. Marugan, Samarjit Patnaik, Udo Rudloff, Noel Southall, Debra Gilbert, Sui Huang, Chen Wang, Zachary Knotts, Christopher R. Dextras, Amy Wang, Stephanie Springer, Serguei Kozlov, Catherine Drennan, Marc Ferrer, Tomas Vilimas, Theresa Guerin, Kevin J. Frankowski, Jerome J. Schlomer, Emma Hughes, Marc D. Singleton, Xin Xu, Dandan Li
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Hepatocyte Nuclear Factor 3-alpha
Cancer Research
Cmax
Administration
Oral
Antineoplastic Agents
Mice
Transgenic
Pharmacology
Toxicology
KPC mice
03 medical and health sciences
Mice
0302 clinical medicine
Pharmacokinetics
Pancreatic cancer
Cell Line
Tumor
medicine
Animals
Humans
Pharmacology (medical)
Pyrroles
Tissue Distribution
Metarrestin
Volume of distribution
Organelles
Perinucleolar compartment
Dose-Response Relationship
Drug
Chemistry
Forkhead Transcription Factors
Peri-nucleolar compartment (PNC)
medicine.disease
3. Good health
Bioavailability
Mice
Inbred C57BL
Pancreatic Neoplasms
030104 developmental biology
Pyrimidines
Oncology
Pharmacodynamics
Organ Specificity
030220 oncology & carcinogenesis
Area Under Curve
Cancer cell
Injections
Intravenous
Original Article
Half-Life
Zdroj: Cancer Chemotherapy and Pharmacology
ISSN: 1432-0843
0344-5704
Popis: 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. Electronic supplementary material The online version of this article (10.1007/s00280-018-3699-0) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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