Original Article

Preclinical pharmacokinetics of TPN729MA, a novel PDE5 inhibitor, and prediction of its human pharmacokinetics using a PBPK model

Zhi-wei GAO, Yun-ting ZHU, Ming-ming YU, Bin ZAN, Jia LIU, Yi-fan ZHANG, Xiao-yan CHEN, Xue-ning LI, Da-fang ZHONG
DOI: 10.1038/aps.2015.118


Aim: 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 (Vss) 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 Tmax, Cmax and AUC values were within 2-fold of the observed values.
Conclusion: 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.
Keywords: TPN729MA; PDE5 inhibitor; erectile dysfunction; pharmacokinetics; human PK prediction; physiologically based pharmacokinetic model

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