Clinical Drug Investigation

, Volume 39, Issue 1, pp 85–96 | Cite as

Pharmacokinetics, Safety and Tolerability of Tylerdipine Hydrochloride, a Novel Dihydropyridine Dual L/T-type Calcium Channel Blocker, after Single and Multiple Oral Doses in Healthy Chinese Subjects

  • Sufeng Zhou
  • Yuanyuan Wang
  • Lu Wang
  • Lijun Xie
  • Juan Chen
  • Yun Liu
  • Hongwen Zhang
  • Yuqing Zhao
  • Ning Ou
  • Feng ShaoEmail author
Original Research Article


Background and Objective

Tylerdipine hydrochloride (KBP-5660) is a novel L/T-type dual calcium channel blocker developed for the treatment of hypertension. We aimed to study the pharmacokinetics, safety and tolerability of tylerdipine in healthy Chinese subjects.


Two double-blind, randomized, dose-escalation studies were conducted that included a total of 88 healthy subjects: (1) a single-ascending dose (SAD) study; and (2) a multiple-ascending dose (MAD) study. In the SAD study, 64 subjects were randomly assigned to receive a single dose of 0.5, 2.5, 5, 10, 15, 20, 25, or 30 mg of tylerdipine or placebo. In the MAD study, 24 subjects were randomly assigned to receive 10 or 20 mg of tylerdipine or placebo once daily for 9 days. Blood samples were collected at the designated time points for pharmacokinetic analyses. Safety assessments were conducted throughout the study.


Following a single oral dose of tylerdipine of 5–30 mg, the mean maximum plasma concentration (Cmax) increased from 0.9993 to 10.11 ng/ml; mean area under the plasma-concentration curve (AUC) from time zero to 72 h increased from 4.332 to 73.95 h·ng/ml. AUC increased in a greater than dose-proportional manner, whereas Cmax exhibited a rough but non-typical dose-proportionality increase. In the MAD study, steady-state conditions were achieved after 1 week of daily dosing in both dose groups. Accumulation of tylerdipine was low, with accumulation ratios (RAUC) of less than 1.65. All adverse events were assessed as mild or moderate.


Tylerdipine hydrochloride was safe and well tolerated. The exposure (AUC) of tylerdipine over the dose range of 5–30 mg increased in a greater than dose-proportional manner, while Cmax exhibited a rough but non-typical dose proportionality increase. A slight accumulation of tylerdipine was observed following multiple dosing.

Study registrations

CTR20140862 and CTR20150660.



The authors thank all the subjects who participated in the studies. This work was supported by the XuanZhu Pharma Co., Ltd. (Jinan, China).

Compliance with Ethical Standards


This study was funded by Xuan Zhu Pharma Co., Ltd. (Jinan, China).

Conflict of interest

The authors have no potential conflicts of interest to report.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The studies were approved by the Ethics Committee of the First Affiliated Hospital with Nanjing Medical University (Nanjing, China) and the approval numbers are 2014-MD-164.A1 for SAD study and 2015-MD-141 for MAD study, respectively.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Chen BL, Zhang YZ, Luo JQ, Zhang W. Clinical use of azelnidipine in the treatment of hypertension in Chinese patients. Ther Clin Risk Manag. 2015;11:309–17.Google Scholar
  2. 2.
    Picon RV, Fuchs FD, Moreira LB, Riegel G, Fuchs SC. Trends in prevalence of hypertension in brazil: a systematic review with meta-analysis. PLoS One. 2012;7(10):e48255.CrossRefGoogle Scholar
  3. 3.
    Jarari N, Rao N, Peela JR, Ellafi KA, Shakila S, Said AR, Nelapalli NK, Min Y, Tun KD, Jamallulail SI, Rawal AK, Ramanujam R, Yedla RN, Kandregula DK, Argi A, Peela LT. A review on prescribing patterns of antihypertensive drugs. Clin Hypertens. 2015;22:7.CrossRefGoogle Scholar
  4. 4.
    Wenzel RR. Renal protection in hypertensive patients: selection of antihypertensive therapy. Drugs. 2005;65:29–39.CrossRefGoogle Scholar
  5. 5.
    Zisaki A, Miskovic L, Hatzimanikatis V. Antihypertensive drugs metabolism: an update to pharmacokinetic profiles and computational approaches. Curr Pharm Des. 2015;21:806–22.CrossRefGoogle Scholar
  6. 6.
    Wang AL, Iadecola C, Wang G. New generations of dihydropyridines for treatment of hypertension. J Geriatr Cardiol. 2017;14:67–72.Google Scholar
  7. 7.
    Dingemanse J, Otasevic P, Shakeri-Nejad K, Klainman E, Putnikovic B, Kracker H, Mueller MS, Zimlichman R. Efficacy and safety of the dual L- and T-type calcium channel blocker, ACT-280778: a proof-of-concept study in patients with mild-to-moderate essential hypertension. J Hum Hypertens. 2015;29:229–35.CrossRefGoogle Scholar
  8. 8.
    Masumiya H, Shijuku T, Tanaka H, Shigenobu K. Inhibition of myocardial L- and T-type Ca2+ currents by efonidipine: possible mechanism for its chronotropic effect. Eur J Pharmacol. 1998;349:351–7.CrossRefGoogle Scholar
  9. 9.
    Ohishi M, Takagi T, Ito N, Terai M, Tatara Y, Hayashi N, Shiota A, Katsuya T, Rakugi H, Ogihara T. Renal-protective effect of T-and L-type calcium channel blockers in hypertensive patients: an Amlodipine-to-Benidipine Changeover (ABC) study. Hypertens Res. 2007;30:797–806.CrossRefGoogle Scholar
  10. 10.
    Ishibashi H, Murai Y, Akaike N. Effect of nilvadipine on the voltage-dependent Ca2+ channels in rat hippocampal CA1 pyramidal neurons. Brain Res. 1998;813:121–7.CrossRefGoogle Scholar
  11. 11.
    Oh IY, Seo MK, Lee HY, Kim SG, Kim KS, Kim WH, Hyon MS, Han KR, Lim SJ, Kim CH. Beneficial effect of efonidipine, an L- and T-type dual calcium channel blocker, on heart rate and blood pressure in patients with mild-to-moderate essential hypertension. Korean Circ J. 2010;40:514–9.CrossRefGoogle Scholar
  12. 12.
    Hayashi K, Wakino S, Sugano N, Ozawa Y, Homma K, Saruta T. Ca2+ channel subtypes and pharmacology in the kidney. Circ Res. 2007;100:342–53.CrossRefGoogle Scholar
  13. 13.
    Hayashi K. L-/T-type Ca channel blockers for kidney protection: ready for sophisticated use of Ca channel blockers. Hypertens Res. 2011;34:910–2.CrossRefGoogle Scholar
  14. 14.
    Hansen PB. Functional importance of T-type voltage-gated calcium channels in the cardiovascular and renal system -news from the world of knock-out mice. Am J Physiol Regul Integr Comp Physiol. 2015;308:227–37.CrossRefGoogle Scholar
  15. 15.
    Zhou S, Tao M, Wang Y, Lu W, Xie L, Chen J, Zhao Y, Yun L, Zhang H, Ning O. Effects of CYP3A4*1G and CYP3A5*3 Polymorphisms on Pharmacokinetics of Tylerdipine hydrochloride in Healthy Chinese Subjects. Xenobiotica. 2018;28:1–6.Google Scholar
  16. 16.
    Boxenbaum H, Battle M. Effective half-life in clinical pharmacology. J Clin Pharmacol. 1995;35:763–6.CrossRefGoogle Scholar
  17. 17.
    Wang H, Ou N, Lang L, Shi R, Hu P, Jiang J. Pharmacokinetics and pharmacodynamics of intravenous ilaprazole in healthy subjects after single ascending doses. Xenobiotica. 2016;46:1133–41.CrossRefGoogle Scholar
  18. 18.
    Liu MY, Jingying Jia M, Gangyi Liu M, Li S, Chuan LuB, Yanmei Liu M, Yu MC. Pharmacokinetics and bioequivalence evaluation of two formulations of 10-mg amlodipine besylate: An open-label, single-dose, randomized, two-way crossover study in healthy chinese male volunteers. Clin Ther. 2009;31:777–83.CrossRefGoogle Scholar
  19. 19.
    US Food and Drug Administration. Safety testing of drug metabolites guidance for industry. 2016. regulatoryinformation/guidances/ucm079266.pdf. Accessed 22 Nov 2016.
  20. 20.
    Jiang J, Li L, Yin H, Woessner R, Emotte C, Li R, Khindri S, Pei H. Single- and multiple-dose pharmacokinetics of inhaled indacaterol in healthy Chinese volunteers. Eur J Drug Metab Pharmacokinet. 2015;40:203–8.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Sufeng Zhou
    • 1
  • Yuanyuan Wang
    • 1
  • Lu Wang
    • 1
  • Lijun Xie
    • 1
  • Juan Chen
    • 1
  • Yun Liu
    • 1
  • Hongwen Zhang
    • 1
  • Yuqing Zhao
    • 1
  • Ning Ou
    • 1
  • Feng Shao
    • 1
    Email author
  1. 1.Phase I Clinical Trial UnitThe First Affiliated Hospital with Nanjing Medical UniversityNanjingChina

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