Pharmacokinetics, pharmacodynamics, and safety of clevidipine after prolonged continuous infusion in subjects with mild to moderate essential hypertension

William Smith, Thomas C. Marbury, Steven F. Komjathy, Mark S. Sumeray, Gregory C. Williams, Ming Yi Hu, Diane R. Mould

Research output: Contribution to journalArticle

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Abstract

Purpose Clevidipine is a rapidly-acting intravenous dihydropyridine antihypertensive acting via calcium channel blockade. This was a randomized, single-blind, parallel-design study of a 72-h continuous clevidipine infusion. Method Doses of 2, 4, 8, or 16.0 mg/h or placebo were evaluated in 61 subjects with mild to moderate essential hypertension. IV clevidipine or placebo was initiated at 2.0 mg/h and force-titrated in doubling increments every 3 min to target dose, then maintained for 72 h. Blood pressure and heart rate were measured during infusion, and for 4, 6 and 8 h after termination of infusion, although oral therapy could be restarted at 4 h. Clevidipine blood levels were obtained during infusion and for 1 hour after termination. Results Rapid onset of drug effect occurred at all clevidipine dose levels, with consistent pharmacokinetics and rapid offset after 72-h infusion. No evidence of tolerance to the clevidipine drug effect was observed at any dose level over the 72-h infusion. No evidence of rebound hypertension was found for either 4 or 6 h after termination of the clevidipine infusion. At 8 h following cessation of clevidipine, blood pressure was not significantly higher than at baseline. Placebo-treated subjects had blood pressures lower than baseline at 8 h following infusion termination; hence, placebo-adjusted blood pressures tended to be slightly higher than baseline. Conclusion This study supports the use of up to 72 h of IV clevidipine therapy for the management of blood pressure, with consistent pharmacokinetic/pharmacodynamic characteristics and context insensitive half-life across the dose ranges evaluated.

Original languageEnglish (US)
Pages (from-to)1385-1394
Number of pages10
JournalEuropean Journal of Clinical Pharmacology
Volume68
Issue number10
DOIs
StatePublished - Oct 1 2012

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Pharmacokinetics
Safety
Blood Pressure
Placebos
Essential Hypertension
clevidipine
Calcium Channels
Pharmaceutical Preparations
Antihypertensive Agents
Half-Life
Heart Rate
Hypertension
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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Pharmacokinetics, pharmacodynamics, and safety of clevidipine after prolonged continuous infusion in subjects with mild to moderate essential hypertension. / Smith, William; Marbury, Thomas C.; Komjathy, Steven F.; Sumeray, Mark S.; Williams, Gregory C.; Hu, Ming Yi; Mould, Diane R.

In: European Journal of Clinical Pharmacology, Vol. 68, No. 10, 01.10.2012, p. 1385-1394.

Research output: Contribution to journalArticle

Smith, William ; Marbury, Thomas C. ; Komjathy, Steven F. ; Sumeray, Mark S. ; Williams, Gregory C. ; Hu, Ming Yi ; Mould, Diane R. / Pharmacokinetics, pharmacodynamics, and safety of clevidipine after prolonged continuous infusion in subjects with mild to moderate essential hypertension. In: European Journal of Clinical Pharmacology. 2012 ; Vol. 68, No. 10. pp. 1385-1394.
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N2 - Purpose Clevidipine is a rapidly-acting intravenous dihydropyridine antihypertensive acting via calcium channel blockade. This was a randomized, single-blind, parallel-design study of a 72-h continuous clevidipine infusion. Method Doses of 2, 4, 8, or 16.0 mg/h or placebo were evaluated in 61 subjects with mild to moderate essential hypertension. IV clevidipine or placebo was initiated at 2.0 mg/h and force-titrated in doubling increments every 3 min to target dose, then maintained for 72 h. Blood pressure and heart rate were measured during infusion, and for 4, 6 and 8 h after termination of infusion, although oral therapy could be restarted at 4 h. Clevidipine blood levels were obtained during infusion and for 1 hour after termination. Results Rapid onset of drug effect occurred at all clevidipine dose levels, with consistent pharmacokinetics and rapid offset after 72-h infusion. No evidence of tolerance to the clevidipine drug effect was observed at any dose level over the 72-h infusion. No evidence of rebound hypertension was found for either 4 or 6 h after termination of the clevidipine infusion. At 8 h following cessation of clevidipine, blood pressure was not significantly higher than at baseline. Placebo-treated subjects had blood pressures lower than baseline at 8 h following infusion termination; hence, placebo-adjusted blood pressures tended to be slightly higher than baseline. Conclusion This study supports the use of up to 72 h of IV clevidipine therapy for the management of blood pressure, with consistent pharmacokinetic/pharmacodynamic characteristics and context insensitive half-life across the dose ranges evaluated.

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