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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

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Abstract

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.

Methods

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.

Results

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.

Conclusion

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.

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References

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  4. Wenzel RR. Renal protection in hypertensive patients: selection of antihypertensive therapy. Drugs. 2005;65:29–39.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang AL, Iadecola C, Wang G. New generations of dihydropyridines for treatment of hypertension. J Geriatr Cardiol. 2017;14:67–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. Boxenbaum H, Battle M. Effective half-life in clinical pharmacology. J Clin Pharmacol. 1995;35:763–6.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  19. US Food and Drug Administration. Safety testing of drug metabolites guidance for industry. 2016. http://www.fda.gov/downloads/drugs/guidancecompliance regulatoryinformation/guidances/ucm079266.pdf. Accessed 22 Nov 2016.

  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.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgement

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

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Authors and Affiliations

  1. Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China

    Sufeng Zhou, Yuanyuan Wang, Lu Wang, Lijun Xie, Juan Chen, Yun Liu, Hongwen Zhang, Yuqing Zhao, Ning Ou & Feng Shao

Authors
  1. Sufeng Zhou
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  2. Yuanyuan Wang
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  3. Lu Wang
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  4. Lijun Xie
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  5. Juan Chen
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  6. Yun Liu
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  7. Hongwen Zhang
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  8. Yuqing Zhao
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  9. Ning Ou
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  10. Feng Shao
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Corresponding author

Correspondence to Feng Shao.

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Funding

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.

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Zhou, S., Wang, Y., Wang, L. et al. 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. Clin Drug Investig 39, 85–96 (2019). https://doi.org/10.1007/s40261-018-0722-5

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