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

Gao ZW, Zhu YT, Yu MM, Zan B, Liu J, Zhang YF, Chen XY, Li XN, Zhong DF - Acta Pharmacol. Sin. (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

ABSTRACT

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 (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.

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.

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Related in: MedlinePlus

Chemical structure of TPN729MA.
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fig1: Chemical structure of TPN729MA.

Mentions: TPN729MA (1-methyl-5-[2-propoxy-5-[N-methyl-N-[2-(pyrrolidin-1-yl)ethyl]] aminosulfonyl]phenyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one) (Figure 1), developed by Topharman (Shanghai, China), is a novel, selective PDE5 inhibitor that is currently under clinical development in China for the treatment of ED. This compound is a potent inhibitor of human PDE5 and has a high selectivity for PDE5 compared with other known phosphodiesterases. The median inhibitory concentration (IC50) of TPN729MA for PDE5 is 2.28 nmol/L, which is similar to that of tadalafil (2.35 nmol/L) and lower than that of sildenafil (5.22 nmol/L)9. In addition, TPN729MA significantly increases the maximum intracavernous pressure (ICP) and the ratio of ICP to blood pressure compared with vehicle in rat and dog models of erection9.


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

Gao ZW, Zhu YT, Yu MM, Zan B, Liu J, Zhang YF, Chen XY, Li XN, Zhong DF - Acta Pharmacol. Sin. (2015)

Chemical structure of TPN729MA.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4816229&req=5

fig1: Chemical structure of TPN729MA.
Mentions: TPN729MA (1-methyl-5-[2-propoxy-5-[N-methyl-N-[2-(pyrrolidin-1-yl)ethyl]] aminosulfonyl]phenyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one) (Figure 1), developed by Topharman (Shanghai, China), is a novel, selective PDE5 inhibitor that is currently under clinical development in China for the treatment of ED. This compound is a potent inhibitor of human PDE5 and has a high selectivity for PDE5 compared with other known phosphodiesterases. The median inhibitory concentration (IC50) of TPN729MA for PDE5 is 2.28 nmol/L, which is similar to that of tadalafil (2.35 nmol/L) and lower than that of sildenafil (5.22 nmol/L)9. In addition, TPN729MA significantly increases the maximum intracavernous pressure (ICP) and the ratio of ICP to blood pressure compared with vehicle in rat and dog models of erection9.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

ABSTRACT

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 (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.

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.

Show MeSH
Related in: MedlinePlus