Preclinical pharmacokinetics of TPN729MA, a novel PDE5 inhibitor, and prediction of its human pharmacokinetics using a PBPK model
文献类型：期刊论文
| 作者 | Gao, Zhi-wei1,2 ; Zhu, Yun-ting1; Yu, Ming-ming1; Zan, Bin1; Liu, Jia1; Zhang, Yi-fan1; Chen, Xiao-yan1; Li, Xue-ning2; Zhong, Da-fang1
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2015-12 |
| 卷号 | 36期号:12页码:1528-1536 |
| ISSN号 | 1671-4083 |
| 关键词 | TPN729MA PDE5 inhibitor erectile dysfunction pharmacokinetics human PK prediction physiologically based pharmacokinetic model |
| DOI | 10.1038/aps.2015.118 |
| 文献子类 | Article |
| 英文摘要 | 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. |
| WOS关键词 | HUMAN DRUG CLEARANCE ; PHOSPHODIESTERASE-5 INHIBITORS ; CLINICAL PHARMACOKINETICS ; ERECTILE DYSFUNCTION ; TISSUE DISTRIBUTION ; ORAL PHARMACOKINETICS ; RECEPTOR ANTAGONIST ; DIVERSE COMPOUNDS ; IN-VIVO ; ABSORPTION |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:5586902 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| WOS记录号 | WOS:000366098300016 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276309]  |
| 专题 | 上海药物代谢研究中心 |
| 通讯作者 | Li, Xue-ning |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.Fudan Univ, Zhongshan Hosp, Dept Clin Pharmacol, Shanghai 200032, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Gao, Zhi-wei,Zhu, Yun-ting,Yu, Ming-ming,et al. Preclinical pharmacokinetics of TPN729MA, a novel PDE5 inhibitor, and prediction of its human pharmacokinetics using a PBPK model[J]. ACTA PHARMACOLOGICA SINICA,2015,36(12):1528-1536. |
| APA | Gao, Zhi-wei.,Zhu, Yun-ting.,Yu, Ming-ming.,Zan, Bin.,Liu, Jia.,...&Zhong, Da-fang.(2015).Preclinical pharmacokinetics of TPN729MA, a novel PDE5 inhibitor, and prediction of its human pharmacokinetics using a PBPK model.ACTA PHARMACOLOGICA SINICA,36(12),1528-1536. |
| MLA | Gao, Zhi-wei,et al."Preclinical pharmacokinetics of TPN729MA, a novel PDE5 inhibitor, and prediction of its human pharmacokinetics using a PBPK model".ACTA PHARMACOLOGICA SINICA 36.12(2015):1528-1536. |
入库方式： OAI收割
来源：上海药物研究所
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