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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

Predicted and observed plasma-concentration-versus-time profiles of TPN729MA after oral administration of 25 mg TPN729MA to healthy volunteers. Observed (cycle) plasma concentration time profiles were obtained from 3 healthy Chinese male subjects after a single oral administration of TPN729MA at 25 mg.
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fig4: Predicted and observed plasma-concentration-versus-time profiles of TPN729MA after oral administration of 25 mg TPN729MA to healthy volunteers. Observed (cycle) plasma concentration time profiles were obtained from 3 healthy Chinese male subjects after a single oral administration of TPN729MA at 25 mg.

Mentions: The predicted human CLp was 12.3 mL·min−1·kg−1 using the in vitro CLint determined in human liver microsomes. The human CLp was predicted to be 10.3, 11.1, 6.42, and 9.53 mL·min−1·kg−1 according to the SSSrat, SSSdog, FCIM, and TSrat-dog methods, respectively. No obvious differences (within 1.3-fold) in the human CL were predicted with the different prediction methods, except for FCIM. It is unclear which value provided a closer estimate of human CL prior to the first in human clinical PK study. These CL estimates were combined with the PBPK model to predict human PK profiles of TPN729MA. The proposed effective dose of TPN729MA in humans (70 kg) extrapolated from the rat efficacious dose of 2.5 mg/kg9 based on body surface area correlation was approximately 25 mg. The human PK of TPN729MA following an oral dose of 25 mg was simulated. The predicted and observed human PK parameters and plasma concentration versus time profiles after oral administration are shown in Figure 4 and Table 5. Overall PBPK modeling reasonably matched the plasma concentration-time profiles of TPN729MA in humans. The predicted PK parameters (Tmax, Cmax, AUC and T1/2) using CL values from the TSrat-dog, SSSrat, and SSSdog methods were within 2-fold of the observed values. The plasma exposures of TPN729MA (AUC) were generally overpredicted using CL from FCIM (2-fold) and underpredicted using CL from HLM (1.9-fold).


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)

Predicted and observed plasma-concentration-versus-time profiles of TPN729MA after oral administration of 25 mg TPN729MA to healthy volunteers. Observed (cycle) plasma concentration time profiles were obtained from 3 healthy Chinese male subjects after a single oral administration of TPN729MA at 25 mg.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Predicted and observed plasma-concentration-versus-time profiles of TPN729MA after oral administration of 25 mg TPN729MA to healthy volunteers. Observed (cycle) plasma concentration time profiles were obtained from 3 healthy Chinese male subjects after a single oral administration of TPN729MA at 25 mg.
Mentions: The predicted human CLp was 12.3 mL·min−1·kg−1 using the in vitro CLint determined in human liver microsomes. The human CLp was predicted to be 10.3, 11.1, 6.42, and 9.53 mL·min−1·kg−1 according to the SSSrat, SSSdog, FCIM, and TSrat-dog methods, respectively. No obvious differences (within 1.3-fold) in the human CL were predicted with the different prediction methods, except for FCIM. It is unclear which value provided a closer estimate of human CL prior to the first in human clinical PK study. These CL estimates were combined with the PBPK model to predict human PK profiles of TPN729MA. The proposed effective dose of TPN729MA in humans (70 kg) extrapolated from the rat efficacious dose of 2.5 mg/kg9 based on body surface area correlation was approximately 25 mg. The human PK of TPN729MA following an oral dose of 25 mg was simulated. The predicted and observed human PK parameters and plasma concentration versus time profiles after oral administration are shown in Figure 4 and Table 5. Overall PBPK modeling reasonably matched the plasma concentration-time profiles of TPN729MA in humans. The predicted PK parameters (Tmax, Cmax, AUC and T1/2) using CL values from the TSrat-dog, SSSrat, and SSSdog methods were within 2-fold of the observed values. The plasma exposures of TPN729MA (AUC) were generally overpredicted using CL from FCIM (2-fold) and underpredicted using CL from HLM (1.9-fold).

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