The Nonclinical Pharmacokinetics and Prediction of Human Pharmacokinetics of SPH3127, a Novel Direct Renin Inhibitor

doi:10.1007/s13318-019-00573-9

	The Nonclinical Pharmacokinetics and Prediction of Human Pharmacokinetics of SPH3127, a Novel Direct Renin Inhibitor
	Zhang, Leduo 2; Mao, Yu 2; Gao, Zhiwei 1; Chen, Xiaoyan 1; Li, Xin 2; Liu, Yanjun 2; Xia, Guangxin 2
刊名	EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS
	2020-02-01
卷号	45 期号:1 页码:15-26
ISSN号	0378-7966
DOI	10.1007/s13318-019-00573-9
通讯作者	Xia, Guangxin(xiagx@sphchina.com)
英文摘要	Background SPH3127 is a novel direct renin inhibitor designed as an oral drug for the regulation of blood pressure and body fluid homeostasis via the renin-angiotensin-aldosterone system (RAAS). This candidate is now being evaluated in a phase I clinical trial in China. Objectives The purpose of this study is to investigate detailed nonclinical pharmacokinetic data, and to predict human pharmacokinetic parameters. Methods In vivo pharmacokinetic studies of SPH3127 were performed to investigate the exposure, absorption, clearance, distribution and metabolism after intravenous and oral administration in rats, beagle dogs and cynomolgus monkeys. The cynomolgus monkey pharmacokinetics/pharmacodynamics study was conducted to investigate the effect-concentration relationship of SPH3127. Its human pharmacokinetic properties were predicted employing an allometric scaling approach based on non-clinical species data. In vitro studies were also employed in a cytochrome P450 (CYP) enzyme phenotyping study, an inhibition and induction study, and a Caco-2 cell permeation and metabolites profile analysis. Results After a single intravenous administration of SPH3127 in rats and monkeys, high clearance and volume of distribution and a short terminal elimination half-life were seen for both species. The oral bioavailability of SPH3127 to rats and monkeys was about 11.5-24.5% and 3.3-11.3%, respectively, with the short peak time, T-max, ranging from 0.25 to 1.3 h. SPH3127 shows low permeability across Caco-2 cell membranes, and as the substrate of p-gp with apparent efflux characteristics. SPH3127 is mainly distributed in the gastrointestine, liver, kidney, pancreas and lung after oral dose in rats, and which decreased quickly to a 1% peak concentration during 12 h. The plasma protein binding ratio of SPH3127 is low as 11.7-14.8% for all species. Excretion studies in rats suggested that fecal, urine and bile excretion represented about 15% of the intake dose, indicating that SPH3127 undergoes extensive metabolism after oral dosing. Phenotyping data revealed that CYP3A4 was the most active enzyme catalyzing the metabolism of SPH3127. The key metabolites were likely N-hydroxylation (M8-7), mono-oxidation-dehydrogenation (M7-4) and mono-oxidation (M8-1, M8-2), both for in vitro liver microsome incubation of all species and in vivo results in rats. The in vitro CYP inhibition study only found very weak action for CYP3A4 (midazolam 1 '-hydroxylation) and CYP3A4 (midazolam 6 beta-hydroxylation) with IC50 of 56.8 mu M and 41.1 mu M, respectively. Monkey pharmacokinetic/pharmacodynamic data showed favorable safety margins when compared with the exposure of the effect dose and that of the monkey NOAEL level. Simple four-species allometric scaling led to predicted human plasma clearance and volume of distribution, and then simulated the oral human plasma concentration-time profile, which are both in good consistency with phase I clinical trial pharmacokinetic data. Conclusions SPH 3127 has appropriate pharmacokinetic properties for further clinical exploration.
WOS关键词	ALISKIREN ; PARAMETERS ; HYPERTENSION ; EFFICACY ; SAFETY
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	SPRINGER FRANCE
WOS记录号	WOS:000513217600002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281735]
专题	中国科学院上海药物研究所
通讯作者	Xia, Guangxin
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.Shanghai Pharmaceut Holding Co Ltd, Cent Res Inst, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Leduo,Mao, Yu,Gao, Zhiwei,et al. The Nonclinical Pharmacokinetics and Prediction of Human Pharmacokinetics of SPH3127, a Novel Direct Renin Inhibitor[J]. EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS,2020,45(1):15-26.
APA	Zhang, Leduo.,Mao, Yu.,Gao, Zhiwei.,Chen, Xiaoyan.,Li, Xin.,...&Xia, Guangxin.(2020).The Nonclinical Pharmacokinetics and Prediction of Human Pharmacokinetics of SPH3127, a Novel Direct Renin Inhibitor.EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS,45(1),15-26.
MLA	Zhang, Leduo,et al."The Nonclinical Pharmacokinetics and Prediction of Human Pharmacokinetics of SPH3127, a Novel Direct Renin Inhibitor".EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS 45.1(2020):15-26.