2. Academic Validation
  3. Preclinical pharmacokinetic studies of 3-deazaneplanocin A, a potent epigenetic anticancer agent, and its human pharmacokinetic prediction using GastroPlus™

Preclinical pharmacokinetic studies of 3-deazaneplanocin A, a potent epigenetic anticancer agent, and its human pharmacokinetic prediction using GastroPlus™

  • Eur J Pharm Sci. 2015 Sep 18;77:290-302. doi: 10.1016/j.ejps.2015.06.021.
Feng Sun 1,  Lawrence Lee 2,  Zhiwei Zhang 3,  Xiaochong Wang 3,  Qiang Yu 4,  XiaoQun Duan 5,  Eli Chan 6
Affiliations

Affiliations

  • 1 Department of Pharmacy, National University of Singapore, 18 Science Drive, Singapore 117543, Singapore; Department of Obstetrics & Gynaecology, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore.
  • 2 Department of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore.
  • 3 Department of Obstetrics & Gynaecology, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore.
  • 4 Cancer Biology and Pharmacology, Genome Institute of Singapore, A(*)STAR (Agency for Science, Technology and Research), Biopolis, Singapore.
  • 5 Department of Pharmacology, Guilin Medical University, 109 Huancheng Road, Guilin 541004, PR China; Department of Obstetrics & Gynaecology, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore. Electronic address: [email protected].
  • 6 Department of Pharmacy, National University of Singapore, 18 Science Drive, Singapore 117543, Singapore. Electronic address: [email protected].
PMID: 26116990 DOI: 10.1016/j.ejps.2015.06.021
Abstract

DZNep is a potential epigenetic drug, and exerts potent anti-proliferative and pro-apoptotic effects on broad-spectrum carcinomas via disruption of the EZH2 pathway. Antitumor studies on DZNep have been stuck in the preclinical phase because of the lack of information about its integral pharmacokinetic (PK) properties. To circumvent this problem, we extensively investigated the disposition characteristics of the DZNep in rats. By incorporating the disposition data across species into a whole-body physiologically based pharmacokinetic (PBPK) models using the GastroPlus(TM) software, we simulated human PK properties of DZNep and determined whether DZNep could be developed for human Cancer therapy. Firstly, DZNep was found to cause nephrotoxicity in a dose-dependent manner in rats and its safe dose was determined to be 10mg/kg. DZNep showed a short plasma elimination half-life (1.1h) in rats, a low protein binding in plasma (18.5%), a low partitioning to erythrocyte (0.78), and a low intrinsic hepatic clearance in rats and humans. There was extensive tissue distribution and predominant renal excretion (80.3%). The simulated rat PBPK model of DZNep was well-verified with satisfactory coefficients of determination for all the tested tissues (R(2)>0.781). The simulated human PBPK model successfully identified that intravenous administration of DZNep at appropriate dosing regimen could be further developed for human non-small cell lung carcinoma treatments. The present findings provide valuable information regarding experimental or in silico PK characteristics of DZNep in rats and humans, which is helpful to guide future studies of DZNep in both preclinical and clinical phases.

Keywords

3-Deazaneplanocin A; GastroPlus; Human non-small cell lung carcinoma; Physiologically based pharmacokinetic models.

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