Pharmacokinetics and safety of clevidipine butyrate injectable emulsion in Chinese healthy subjects_West China Medical Journal

Authors：

HE Yongji , YANG Ling , ZHU Xiaohong , WANG Ying ,  LUO Zhu

Clinical Trial Center / National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LUO Zhu, Email: luozhu720@163.com

Keywords：

Clevidipine; Chinese healthy subjects; pharmacokinetics; safety

DOI：

10.7507/1002-0179.202503008

Video：

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Objective To investigate the pharmacokinetic profiles and safety of clevidipine butyrate injectable emulsion in Chinese healthy subjects, following intravenous administration with gradually increasing doses. Methods From June to July 2020, 12 Chinese healthy adult subjects were enrolled in the single-center, single-arm, open-label clinical trial. The gradually increasing doses were 1, 2, 4 and 6 mg/h, starting with the initial infusion rate of 1 mg/h. Each dose was infused for 2 min before increasing to the next dose. After reaching 6 mg/h, the infusion rate was maintained for 20 min. Plasma concentrations of clevidipine and its metabolite H152/81 were detected using high performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental analysis using WinNonlin 8.0. Data following a normal distribution were presented as mean ± standard deviation, while data following a log-normal distribution were presented as geometric mean ×/÷ geometric standard deviation. Results Pharmacokinetic parameters of clevidipine were as follows: elimination half-life (t_1/2) (3.79×/÷2.35) min, peak concentration (C_max) (11.71±3.79) ng/mL, area under concentration-time curve from time 0 to the last measurable concentration (AUC_0–t) (222.89±61.79) min·ng/mL, area under concentration-time curve from time 0 extrapolated to infinite time (AUC_0–∞) (233.35±78.64) min·ng/mL, and median time to peak concentration (T_max) 18.00 min. Pharmacokinetic parameters of H152/81 were as follows: t_1/2 (194.68×/÷1.42) min, C_max (162.00±23.35) ng/mL, AUC_0–t (12794.40±1976.56) min·ng/mL, AUC_0–∞ (41215.86±10110.90) min·ng/mL, and median T_max 31.00 min. Following the administration, clevidipine rapidly affected heart rate and blood pressure. The heart rates of subjects increased slightly, and the decrease in diastolic blood pressure was greater than that in systolic blood pressure. The effects disappeared within 4 min after the infusion ended. Only 1 mild adverse event was reported. Conclusion Clevidipine shows a short half-life, as well as good safety and tolerability in Chinese healthy subjects.

1.	McEvoy JW, McCarthy CP, Bruno RM, et al. 2024 ESC Guidelines for the management of elevated blood pressure and hypertension. Eur Heart J, 2024, 45(38): 3912-4018.
2.	刘明波, 何新叶, 杨晓红, 等. 《中国心血管健康与疾病报告 2023》要点解读. 中国心血管杂志, 2024, 29(4): 305-324.
3.	Carey RM, Wright JT Jr, Taler SJ, et al. Guideline-driven management of hypertension: an evidence-based update. Circ Res, 2021, 128(7): 827-846.
4.	Mahfoud F, Schlaich MP, Lobo MD. Device therapy of hypertension. Circ Res, 2021, 128(7): 1080-1099.
5.	中国高血压防治指南修订委员会, 高血压联盟(中国), 中国医疗保健国际交流促进会高血压分会, 等. 中国高血压防治指南(2024 年修订版). 中华高血压杂志, 2024, 32(7): 603-700.
6.	Keating GM. Clevidipine: a review of its use for managing blood pressure in perioperative and intensive care settings. Drugs, 2014, 74(16): 1947-1960.
7.	Bekker A, Didehvar S, Kim S, et al. Efficacy of clevidipine in controlling perioperative hypertension in neurosurgical patients: initial single-center experience. J Neurosurg Anesthesiol, 2010, 22(4): 330-335.
8.	Aronson S, Dyke CM, Stierer KA, et al. The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients. Anesth Analg, 2008, 107(4): 1110-1121.
9.	Xu B, Chen Z, Tang G. The current role of clevidipine in the management of hypertension. Am J Cardiovasc Drugs, 2022, 22(2): 127-139.
10.	杨克旭, 荆珊, 鲁春艳, 等. 单剂量口服盐酸卡利哌嗪在健康成年人中的药代动力学研究. 中国临床药理学杂志, 2022, 38(11): 1242-1246.
11.	Ericsson H, Fakt C, Jolin-Mellgård A, et al. Clinical and pharmacokinetic results with a new ultrashort-acting calcium antagonist, clevidipine, following gradually increasing intravenous doses to healthy volunteers. Br J Clin Pharmacol, 1999, 47(5): 531-538.
12.	Zhang Y, Zhao S, Zhou H, et al. Development and validation of samples stabilization strategy and LC-MS/MS method for simultaneous determination of clevidipine and its primary metabolite in human plasma: application to clinical pharmacokinetic study in Chinese healthy volunteers. J Chromatogr B Analyt Technol Biomed Life Sci, 2020, 1161: 122448.
13.	Ericsson H, Bredberg U, Eriksson U, et al. Pharmacokinetics and arteriovenous differences in clevidipine concentration following a short- and a long-term intravenous infusion in healthy volunteers. Anesthesiology, 2000, 92(4): 993-1001.
14.	Ericsson H, Fakt C, Höglund L, et al. Pharmacokinetics and pharmacodynamics of clevidipine in healthy volunteers after intravenous infusion. Eur J Clin Pharmacol, 1999, 55(1): 61-67.
15.	Li P, Wu H, Zhao Z, et al. Simultaneous quantitation of clevidipine and its active metabolite H152/81 in human whole blood by LC-MS/MS: application to bioequivalence study. Front Chem, 2022, 10: 861952.
16.	Wang Y, Zhao L, Li T, et al. Pharmacokinetics and tissue distribution study of clevidipine and its primary metabolite H152/81 in rats. Biomed Chromatogr, 2018, 32(2): e4048.
17.	Levy JH, Mancao MY, Gitter R, et al. Clevidipine effectively and rapidly controls blood pressure preoperatively in cardiac surgery patients: the results of the randomized, placebo-controlled efficacy study of clevidipine assessing its preoperative antihypertensive effect in cardiac surgery-1. Anesth Analg, 2007, 105(4): 918-925.
18.	Varelas PN, Abdelhak T, Corry JJ, et al. Clevidipine for acute hypertension in patients with subarachnoid hemorrhage: a pilot study. Int J Neurosci, 2014, 124(3): 192-198.
19.	Graffagnino C, Bergese S, Love J, et al. Clevidipine rapidly and safely reduces blood pressure in acute intracerebral hemorrhage: the ACCELERATE trial. Cerebrovasc Dis, 2013, 36(3): 173-180.
20.	Singla N, Warltier DC, Gandhi SD, et al. Treatment of acute postoperative hypertension in cardiac surgery patients: an efficacy study of clevidipine assessing its postoperative antihypertensive effect in cardiac surgery-2 (ESCAPE-2), a randomized, double-blind, placebo-controlled trial. Anesth Analg, 2008, 107(1): 59-67.
21.	Bailey JM, Lu W, Levy JH, et al. Clevidipine in adult cardiac surgical patients: a dose-finding study. Anesthesiology, 2002, 96(5): 1086-1094.
22.	van den Born BH, Lip GYH, Brguljan-Hitij J, et al. ESC Council on hypertension position document on the management of hypertensive emergencies. Eur Heart J Cardiovasc Pharmacother, 2019, 5(1): 37-46.
23.	Espinosa A, Ripollés-Melchor J, Casans-Francés R, et al. Perioperative use of clevidipine: a systematic review and meta-analysis. PLoS One, 2016, 11(3): e0150625.
24.	Powroznyk AV, Vuylsteke A, Naughton C, et al. Comparison of clevidipine with sodium nitroprusside in the control of blood pressure after coronary artery surgery. Eur J Anaesthesiol, 2003, 20(9): 697-703.
25.	Alviar CL, Gutierrez A, Cho L, et al. Clevidipine as a therapeutic and cost-effective alternative to sodium nitroprusside in patients with acute aortic syndromes. Eur Heart J Acute Cardiovasc Care, 2020, 9(3_suppl): S5-S12.
26.	Merry AF, Avery EG, Nussmeier NA, et al. Clevidipine compared with nitroglycerin for blood pressure control in coronary artery bypass grafting: a randomized double-blind study. Can J Anaesth, 2014, 61(5): 398-406.
27.	Widiastuti M, Bisri DY, Rachman IA. The safety and efficacy of clevidipine for blood pressure management in neurocritical patients: a systematic review and meta-analysis. Sci Rep, 2024, 14(1): 6355.
28.	Colomy VV, Reinaker TS. Comparative study of clevidipine to nicardipine for perioperative hypertension in patients undergoing cardiac surgery. J Pharm Pract, 2023, 36(3): 501-507.
29.	Chrétien B, Decros JB, Suard F, et al. Hypoxia associated with dihydropyridine calcium channel inhibitors: a pharmacovigilance study in VigiBase. Clin Pharmacol Ther, 2023, 114(3): 686-692.
30.	张艺蓉, 贺佳, 任博, 等. 丁酸氯维地平亚微乳静脉注射液的制备及质量评价. 沈阳药科大学学报, 2023, 40(5): 547-554, 612.
31.	Kaur H, Nattanamai P, Qualls KE. Propofol and clevidipine-induced hypertriglyceridemia. Cureus, 2018, 10(8): e3165.
32.	Ericsson H, Tholander B, Regårdh CG. In vitro hydrolysis rate and protein binding of clevidipine, a new ultrashort-acting calcium antagonist metabolised by esterases, in different animal species and man. Eur J Pharm Sci, 1999, 8(1): 29-37.
33.	Miller JB, Hrabec D, Krishnamoorthy V, et al. Evaluation and management of hypertensive emergency. BMJ, 2024, 386: e077205.

1. McEvoy JW, McCarthy CP, Bruno RM, et al. 2024 ESC Guidelines for the management of elevated blood pressure and hypertension. Eur Heart J, 2024, 45(38): 3912-4018.
2. 刘明波, 何新叶, 杨晓红, 等. 《中国心血管健康与疾病报告 2023》要点解读. 中国心血管杂志, 2024, 29(4): 305-324.
3. Carey RM, Wright JT Jr, Taler SJ, et al. Guideline-driven management of hypertension: an evidence-based update. Circ Res, 2021, 128(7): 827-846.
4. Mahfoud F, Schlaich MP, Lobo MD. Device therapy of hypertension. Circ Res, 2021, 128(7): 1080-1099.
5. 中国高血压防治指南修订委员会, 高血压联盟(中国), 中国医疗保健国际交流促进会高血压分会, 等. 中国高血压防治指南(2024 年修订版). 中华高血压杂志, 2024, 32(7): 603-700.
6. Keating GM. Clevidipine: a review of its use for managing blood pressure in perioperative and intensive care settings. Drugs, 2014, 74(16): 1947-1960.
7. Bekker A, Didehvar S, Kim S, et al. Efficacy of clevidipine in controlling perioperative hypertension in neurosurgical patients: initial single-center experience. J Neurosurg Anesthesiol, 2010, 22(4): 330-335.
8. Aronson S, Dyke CM, Stierer KA, et al. The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients. Anesth Analg, 2008, 107(4): 1110-1121.
9. Xu B, Chen Z, Tang G. The current role of clevidipine in the management of hypertension. Am J Cardiovasc Drugs, 2022, 22(2): 127-139.
10. 杨克旭, 荆珊, 鲁春艳, 等. 单剂量口服盐酸卡利哌嗪在健康成年人中的药代动力学研究. 中国临床药理学杂志, 2022, 38(11): 1242-1246.
11. Ericsson H, Fakt C, Jolin-Mellgård A, et al. Clinical and pharmacokinetic results with a new ultrashort-acting calcium antagonist, clevidipine, following gradually increasing intravenous doses to healthy volunteers. Br J Clin Pharmacol, 1999, 47(5): 531-538.
12. Zhang Y, Zhao S, Zhou H, et al. Development and validation of samples stabilization strategy and LC-MS/MS method for simultaneous determination of clevidipine and its primary metabolite in human plasma: application to clinical pharmacokinetic study in Chinese healthy volunteers. J Chromatogr B Analyt Technol Biomed Life Sci, 2020, 1161: 122448.
13. Ericsson H, Bredberg U, Eriksson U, et al. Pharmacokinetics and arteriovenous differences in clevidipine concentration following a short- and a long-term intravenous infusion in healthy volunteers. Anesthesiology, 2000, 92(4): 993-1001.
14. Ericsson H, Fakt C, Höglund L, et al. Pharmacokinetics and pharmacodynamics of clevidipine in healthy volunteers after intravenous infusion. Eur J Clin Pharmacol, 1999, 55(1): 61-67.
15. Li P, Wu H, Zhao Z, et al. Simultaneous quantitation of clevidipine and its active metabolite H152/81 in human whole blood by LC-MS/MS: application to bioequivalence study. Front Chem, 2022, 10: 861952.
16. Wang Y, Zhao L, Li T, et al. Pharmacokinetics and tissue distribution study of clevidipine and its primary metabolite H152/81 in rats. Biomed Chromatogr, 2018, 32(2): e4048.
17. Levy JH, Mancao MY, Gitter R, et al. Clevidipine effectively and rapidly controls blood pressure preoperatively in cardiac surgery patients: the results of the randomized, placebo-controlled efficacy study of clevidipine assessing its preoperative antihypertensive effect in cardiac surgery-1. Anesth Analg, 2007, 105(4): 918-925.
18. Varelas PN, Abdelhak T, Corry JJ, et al. Clevidipine for acute hypertension in patients with subarachnoid hemorrhage: a pilot study. Int J Neurosci, 2014, 124(3): 192-198.
19. Graffagnino C, Bergese S, Love J, et al. Clevidipine rapidly and safely reduces blood pressure in acute intracerebral hemorrhage: the ACCELERATE trial. Cerebrovasc Dis, 2013, 36(3): 173-180.
20. Singla N, Warltier DC, Gandhi SD, et al. Treatment of acute postoperative hypertension in cardiac surgery patients: an efficacy study of clevidipine assessing its postoperative antihypertensive effect in cardiac surgery-2 (ESCAPE-2), a randomized, double-blind, placebo-controlled trial. Anesth Analg, 2008, 107(1): 59-67.
21. Bailey JM, Lu W, Levy JH, et al. Clevidipine in adult cardiac surgical patients: a dose-finding study. Anesthesiology, 2002, 96(5): 1086-1094.
22. van den Born BH, Lip GYH, Brguljan-Hitij J, et al. ESC Council on hypertension position document on the management of hypertensive emergencies. Eur Heart J Cardiovasc Pharmacother, 2019, 5(1): 37-46.
23. Espinosa A, Ripollés-Melchor J, Casans-Francés R, et al. Perioperative use of clevidipine: a systematic review and meta-analysis. PLoS One, 2016, 11(3): e0150625.
24. Powroznyk AV, Vuylsteke A, Naughton C, et al. Comparison of clevidipine with sodium nitroprusside in the control of blood pressure after coronary artery surgery. Eur J Anaesthesiol, 2003, 20(9): 697-703.
25. Alviar CL, Gutierrez A, Cho L, et al. Clevidipine as a therapeutic and cost-effective alternative to sodium nitroprusside in patients with acute aortic syndromes. Eur Heart J Acute Cardiovasc Care, 2020, 9(3_suppl): S5-S12.
26. Merry AF, Avery EG, Nussmeier NA, et al. Clevidipine compared with nitroglycerin for blood pressure control in coronary artery bypass grafting: a randomized double-blind study. Can J Anaesth, 2014, 61(5): 398-406.
27. Widiastuti M, Bisri DY, Rachman IA. The safety and efficacy of clevidipine for blood pressure management in neurocritical patients: a systematic review and meta-analysis. Sci Rep, 2024, 14(1): 6355.
28. Colomy VV, Reinaker TS. Comparative study of clevidipine to nicardipine for perioperative hypertension in patients undergoing cardiac surgery. J Pharm Pract, 2023, 36(3): 501-507.
29. Chrétien B, Decros JB, Suard F, et al. Hypoxia associated with dihydropyridine calcium channel inhibitors: a pharmacovigilance study in VigiBase. Clin Pharmacol Ther, 2023, 114(3): 686-692.
30. 张艺蓉, 贺佳, 任博, 等. 丁酸氯维地平亚微乳静脉注射液的制备及质量评价. 沈阳药科大学学报, 2023, 40(5): 547-554, 612.
31. Kaur H, Nattanamai P, Qualls KE. Propofol and clevidipine-induced hypertriglyceridemia. Cureus, 2018, 10(8): e3165.
32. Ericsson H, Tholander B, Regårdh CG. In vitro hydrolysis rate and protein binding of clevidipine, a new ultrashort-acting calcium antagonist metabolised by esterases, in different animal species and man. Eur J Pharm Sci, 1999, 8(1): 29-37.
33. Miller JB, Hrabec D, Krishnamoorthy V, et al. Evaluation and management of hypertensive emergency. BMJ, 2024, 386: e077205.

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