RRC ID 54672
著者 Vilimas T, Wang AQ, Patnaik S, Hughes EA, Singleton MD, Knotts Z, Li D, Frankowski K, Schlomer JJ, Guerin TM, Springer S, Drennan C, Dextras C, Wang C, Gilbert D, Southall N, Ferrer M, Huang S, Kozlov S, Marugan J, Xu X, Rudloff U.
タイトル 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.
ジャーナル Cancer Chemother Pharmacol
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.
巻・号 82(6)
ページ 1067-1080
公開日 2018-12-1
DOI 10.1007/s00280-018-3699-0
PII 10.1007/s00280-018-3699-0
PMID 30306263
PMC PMC6267684
MeSH Administration, Oral Animals Antineoplastic Agents / administration & dosage Antineoplastic Agents / blood Antineoplastic Agents / pharmacokinetics* Antineoplastic Agents / therapeutic use Area Under Curve Cell Line, Tumor Dose-Response Relationship, Drug Forkhead Transcription Factors / genetics Half-Life Hepatocyte Nuclear Factor 3-alpha / genetics Humans Injections, Intravenous Mice Mice, Inbred C57BL Mice, Transgenic Organ Specificity Organelles / drug effects* Organelles / metabolism Organelles / pathology Pancreatic Neoplasms / drug therapy* Pancreatic Neoplasms / genetics Pancreatic Neoplasms / metabolism Pancreatic Neoplasms / pathology Pyrimidines / administration & dosage Pyrimidines / blood Pyrimidines / pharmacokinetics* Pyrimidines / therapeutic use Pyrroles / administration & dosage Pyrroles / blood Pyrroles / pharmacokinetics* Pyrroles / therapeutic use Tissue Distribution
IF 3.008
引用数 2
リソース情報
ヒト・動物細胞 PK-59(RCB1901)