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

  • Leduo Zhang
  • Yu Mao
  • Zhiwei Gao
  • Xiaoyan Chen
  • Xin Li
  • Yanjun Liu
  • Guangxin XiaEmail author
Original Research Article
  • 27 Downloads

Abstract

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, Tmax, 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 6β-hydroxylation) with IC50 of 56.8 µM and 41.1 µM, 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.

Notes

Acknowledgements

We are grateful for collaborative efforts from the Mitsubishi Tanabe Pharma Corporation which were made for the identification of SPH3127.

Compliance with Ethical Standards

Ethics Approval

All animal studies were implemented according to protocols, which were reviewed and approved by the Institutional Animal Care and Use Committee at Shanghai Institute of Materia Medica (Shanghai, China).

Funding

This research was funded by: National Major S&T Project for “Significant New Drugs Development” (nos. 2008ZX09401-003; 2010ZX09401-404; 2014ZX09304002-002; 2018ZX09301009-005), International S&T Cooperation Program of China (ISTCP) (no. 2010DFB30610), International S&T Cooperation Program of Shanghai, National Science and Technology Infrastructure Program (CN) (no. 09430711100), and Program of Shanghai Subject Chief Scientist (B type) (no. 15XD1523600).

Conflict of interest

The authors declare that there are no conflicts of interest.

Supplementary material

13318_2019_573_MOESM1_ESM.pdf (6.9 mb)
Supplementary material 1 (PDF 7101 kb)

References

  1. 1.
    Azizi M, Ménard J. Combined blockade of the renin–angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation. 2004;109:2492–9.CrossRefGoogle Scholar
  2. 2.
    Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol. 2007;3(9):486–92.CrossRefGoogle Scholar
  3. 3.
    Hovater MB, Jaimes EA. Optimizing combination therapy in the management of hypertension: the role of the aliskiren, amlodipine, and hydrochlorothiazide fixed combination. Integr Blood Press Control. 2013;6:59–67.Google Scholar
  4. 4.
    Nussberger J, Aubert J-F, Bouzourene K, Pellegrin M, Hayoz D, Mazzolai L. Renin inhibition by aliskiren prevents atherosclerosis progression. Comparison with irbesartan, atenolol, and amlodipine. Hypertension. 2008;51:1306–11.CrossRefGoogle Scholar
  5. 5.
    Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation. 2005;111:1012–8.CrossRefGoogle Scholar
  6. 6.
    Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, doubleblind trial. Lancet. 2007;370:221–9.CrossRefGoogle Scholar
  7. 7.
    Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204–13.CrossRefGoogle Scholar
  8. 8.
    Wang G. Pharmacokinetics. Chemical Industry Press (CIP). ISBN: 9787502573706; 2005.Google Scholar
  9. 9.
    Mahmood I, Martinez M, Hunter RP. Interspecies allometric scaling. Part I: prediction of clearance in large animals. J Vet Pharmacol Ther. 2006;29:415–23.CrossRefGoogle Scholar
  10. 10.
    Niwa T, Murayama N, Emoto C, Yamazaki H. Comparison of kinetic parameters for drug oxidation rates and substrate inhibition potential mediated by cytochrome P450 3A4 and 3A5. Curr Drug Metab. 2008;9:20–33.CrossRefGoogle Scholar
  11. 11.
    Tektuma (Aliskiren) Tablets NDA 021985. Pharmacology review (part 1). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_PharmR_P1.pdf. Accessed 23 Aug 2019.
  12. 12.
    Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993;10:1093–5.CrossRefGoogle Scholar
  13. 13.
    Ward KW, Smith BR. A comprehensive quantitative and qualitative evaluation of extrapolation of intravenous pharmacokinetic parameters from rat, dog, and monkey to humans. I. Clearance. Drug Metab Dispos. 2004;32:603–11.CrossRefGoogle Scholar
  14. 14.
    Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PK, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res. 2003;58:32–45.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Central Research Institute, Shanghai Pharmaceutical Holding Co., Ltd.ShanghaiChina
  2. 2.Shanghai Institute of Materia Medica, Chinese Academy of SciencesShanghaiChina

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