title: Preclinical pharmacokinetics of TPN729MA, a novel PDE5 inhibitor, and prediction of its human pharmacokinetics using a PBPK model.
abstract: OBJECTIVE
  TPN729MA is a novel selective PDE5 inhibitor currently under clinical development in China for the treatment of erectile dysfunction. In this study we characterized its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model.
  
  
  METHODS
  The preclinical PK of TPN729MA was studied in rats and dogs. Human clearance (CL) values for TPN729MA were predicted from various allometric methods and from intrinsic CL determined in human liver microsomes. Human PK and plasma concentration versus time profiles of TPN729MA were predicted by using a PBPK model in GastroPlus. Considering the uncertainties in the prediction, a preliminary human study was conducted in 3 healthy male volunteers with an oral dose of 25 mg.
  
  
  RESULTS
  After a single intravenous administration of TPN729MA at a dose of 1 mg/kg in rats and 3 mg/kg in dogs, the plasma CL was 69.7 mL·min(-1)·kg(-1) in rats and 26.3 mL·min(-1)·kg(-1) in dogs, and the steady-state volumes of distribution (V(ss)) were 7.35 L/kg in rats and 6.48 L/kg in dogs. The oral bioavailability of TPN729MA was 10% in rats and above 34% in dogs. Profiles of predicted plasma concentration versus time were similar to those observed in humans at 25 mg, and the predicted T(max), C(max) and AUC values were within 2-fold of the observed values.
  
  
  CONCLUSIONS
  TPN729MA demonstrates good preclinical PK. This compound is a valuable candidate for further clinical development. This study shows the benefits of using a PBPK model to predict PK in humans.
authors.affiliation: Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.|Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Zhi-wei
authors.initials: ZW
authors.lastname: Gao
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yun-ting
authors.initials: YT
authors.lastname: Zhu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Ming-ming
authors.initials: MM
authors.lastname: Yu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zan
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yi-fan
authors.initials: YF
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xiao-yan
authors.initials: XY
authors.lastname: Chen
authors.affiliation: Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Xue-ning
authors.initials: XN
authors.lastname: Li
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Da-fang
authors.initials: DF
authors.lastname: Zhong
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D004285:Dogs; D007172:Erectile Dysfunction / Q000188:drug therapy; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D058986:Phosphodiesterase 5 Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats
chemical_list: D001798:Blood Proteins; D058986:Phosphodiesterase 5 Inhibitors