Chang Ren1, Yao Wang1, Mei Zhang1, Dexuan Kong1, Chen Ning1, Yujie Cheng1, Yueying Bian1, Mengqi Sun1, Shengdi Su1, Yucong Wang1, Yongjie Zhang1, Yang Lu1, Ning Li2, Di Zhao3, Xijing Chen4. 1. Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, #639 Longmian Avenue, Jiangning District, Nanjing, 211198, China. 2. National Experimental Teaching Demonstration Center of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. 3. Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, #639 Longmian Avenue, Jiangning District, Nanjing, 211198, China. zh_d99@cpu.edu.cn. 4. Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, #639 Longmian Avenue, Jiangning District, Nanjing, 211198, China. chenxj-lab@hotmail.com.
Abstract
PURPOSE: Sulcardine sulfate (Sul) is a novel antiarrhythmic agent with promising pharmacological properties, which is currently being evaluated in several clinical trials as an oral formulation. To meet the medication needs of patients with acute conditions, the injection formulation of Sul has been developed. The objective of this study was to systemically investigate the pharmacokinetic profiles of Sul after intravenous infusion. METHODS: This research included the plasma protein binding and metabolic stability studies in vitro, plasma pharmacokinetics, biodistribution, excretion studies in animals, and the prediction of the clinical PK of Sul injection using a physiologically based pharmacokinetics (PBPK) model. RESULTS: The metabolic stability was similarly in dogs and humans but lower in rats. The plasma protein binding rates showed a concentration-dependent manner and species differences. The pharmacokinetic behavior after intravenous administration was linear in rats within the dose range of 30-90 mg/kg, but nonlinear in dogs within 30-60 mg/kg. Sul could be rapidly and widely distributed in multiple tissues after intravenous administration. About 12% of the parent compound were excreted via the urine and only a small fraction via bile and feces,and eight metabolites were found and identified in the rat excretion. The PBPK models were developed and simulated the observed PK date well in both rats and dogs. The PBPK model refined with human data predicted the PK characteristics of the first intravenous infusion of Sul in human. CONCLUSIONS: Our study systematically explored the pharmacokinetic characteristics of Sul and successfully developed the PBPK model to predict of its clinical PK.
PURPOSE: Sulcardine sulfate (Sul) is a novel antiarrhythmic agent with promising pharmacological properties, which is currently being evaluated in several clinical trials as an oral formulation. To meet the medication needs of patients with acute conditions, the injection formulation of Sul has been developed. The objective of this study was to systemically investigate the pharmacokinetic profiles of Sul after intravenous infusion. METHODS: This research included the plasma protein binding and metabolic stability studies in vitro, plasma pharmacokinetics, biodistribution, excretion studies in animals, and the prediction of the clinical PK of Sul injection using a physiologically based pharmacokinetics (PBPK) model. RESULTS: The metabolic stability was similarly in dogs and humans but lower in rats. The plasma protein binding rates showed a concentration-dependent manner and species differences. The pharmacokinetic behavior after intravenous administration was linear in rats within the dose range of 30-90 mg/kg, but nonlinear in dogs within 30-60 mg/kg. Sul could be rapidly and widely distributed in multiple tissues after intravenous administration. About 12% of the parent compound were excreted via the urine and only a small fraction via bile and feces,and eight metabolites were found and identified in the rat excretion. The PBPK models were developed and simulated the observed PK date well in both rats and dogs. The PBPK model refined with human data predicted the PK characteristics of the first intravenous infusion of Sul in human. CONCLUSIONS: Our study systematically explored the pharmacokinetic characteristics of Sul and successfully developed the PBPK model to predict of its clinical PK.
Authors: Natilie A Hosea; Wendy T Collard; Susan Cole; Tristan S Maurer; Rick X Fang; Hannah Jones; Shefali M Kakar; Yasuhiro Nakai; Bill J Smith; Rob Webster; Kevin Beaumont Journal: J Clin Pharmacol Date: 2009-03-19 Impact factor: 3.126
Authors: Donglin Guo; Que Liu; Tengxian Liu; Gary Elliott; Mireille Gingras; Peter R Kowey; Gan-Xin Yan Journal: J Cardiovasc Pharmacol Date: 2011-01 Impact factor: 3.105