Pharmacokinetics and pharmacodynamics of two different landiolol formulations in a healthy Caucasian group

Krumpl, Günther; Ulč, Ivan; Trebs, Michaela; Kadlecová, Pavla; Hodisch, Juri

doi:10.1016/j.ejps.2016.06.022

Cited by 13 publications

(11 citation statements)

References 42 publications

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“…The pharmacokinetic results on landiolol and its inactive metabolites were similar to what has been described before in Asian and Caucasian subjects [5,16,37,42,53]. Specifically, the lack of a substantial change in the pharmacokinetic parameters of landiolol during dobutamine infusion confirms that changes in liver perfusion do not affect (and specifically do not speed up) the elimination of landiolol.…”

Section: Pharmacokineticssupporting

confidence: 83%

“…Antagonism of dobutamine-induced tachycardia has been described for esmolol, another short-acting βblocker using bolus application [39,52]. The dose of 10 μg/kg/min landiolol used in the present study produced blood concentrations which correspond to the ones achieved with landiolol bolus doses of 0.1 mg • kg − 1 [53]. As this dose induced an onset of the bradycardic effect within 1 min, it can be assumed that bolus application can reduce the time to maximum HR reduction from the 16 min observed in the current study to few minutes when a rapid termination of the tachycardic dobutamine effect after stress testing is warranted.…”

Section: Pharmacodynamicssupporting

confidence: 63%

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Pharmacodynamic and pharmacokinetic behavior of landiolol during dobutamine challenge in healthy adults

Krumpl¹,

Ulč²,

Trebs

et al. 2020

BMC Pharmacol Toxicol

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Background To study the pharmacokinetic and -dynamic behavior of landiolol in the presence of dobutamine in healthy subjects of European ancestry. Methods We conducted a single-center, prospective randomized study in 16 healthy subjects each receiving an infusion of dobutamine sufficient to increase heart rate by 30 bpm followed by a 60 min infusion of 10 μg/kg/min landiolol. Results Dobutamine-induced increases in heart rate were stable for at least 20 min before a 60 min landiolol- infusion was started. The dobutamine effects were rapidly antagonized by landiolol within 16 min. A further slight decrease in heart rate during 20–60 min of the landiolol infusion occurred as well. Upon termination of landiolol infusion, heart rate and blood pressure recovered rapidly in response to the persisting dobutamine infusion but did not return to the maximum values before landiolol infusion. The pharmacokinetic parameters of landiolol in presence of dobutamine showed a short half-life (3.5 min) and a low distribution volume (0.3 l/kg). No serious adverse events were observed. Conclusion Landiolol can antagonize the dobutamine-induced increases in heart rate and blood pressure in a fast way. A rapid bradycardic effect until steady-state plasma levels is followed by a slow heart rate reduction. The latter can be attributed to an early desensitization to dobutamine. Consequently, after termination of landiolol, the heart rate did not achieve maximum pre-landiolol values. The pharmacokinetics of landiolol during dobutamine infusion are similar when compared to short- and long-term data in Caucasian subjects. Landiolol in the given dose can thus serve as an antagonist of dobutamine-induced cardiac effects. Trial registration Registration number 2010–023311-34 at the EU Clinical Trials Register, registration date 2010-12-21.

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Section: Pharmacokineticssupporting

confidence: 83%

Section: Pharmacodynamicssupporting

confidence: 63%

Pharmacodynamic and pharmacokinetic behavior of landiolol during dobutamine challenge in healthy adults

Krumpl¹,

Ulč²,

Trebs

et al. 2020

BMC Pharmacol Toxicol

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“…12 In hepatically impaired patients, maximum concentration (Cmax) and area under the concentration (AUC)-time curve values were 42% and 44% higher, respectively, but half-life did not differ compared with healthy patients and no drug-related adverse events were observed. 13 A standardized method for detecting pharmacokinetics in plasma with liquid chromatography-tandem mass spectrometry (LC MS-MS) in humans 14 has yielded pharmacokinetics and pharmacodynamics for Japanese, 1 Chinese 15 and Caucasian healthy 16 and acute-phase AF/AFL populations. 17 Table 1 summarizes pharmacokinetics by population.…”

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

<p>Evaluating the Therapeutic Efficacy and Safety of Landiolol Hydrochloride for Management of Arrhythmia in Critical Settings: Review of the Literature</p>

Matsuishi¹,

Mathis²,

Shimojo³

et al. 2020

VHRM

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Background: Landiolol hydrochloride, a highly cardio-selective beta-1 blocker with an ultra-short-acting half-life of 4 minutes, was originally approved by Japan for treatment of intraoperative tachyarrhythmias. This review aims to provide an integrated overview of the current state of knowledge of landiolol hydrochloride in the management of arrhythmia in critical settings. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library to retrieve relevant articles with a total of 65 records identified. Results: The high β1 selectivity (β1/β2 ratio of 255:1) of landiolol causes a more rapid heart rate (HR) decrease compared to esmolol while avoiding decreases in mean arterial blood pressure. Recently, it has been found useful in left ventricular dysfunction patients and fatal arrhythmia requiring emergency treatment. Recent random clinical trials (RCT) have revealed therapeutic and prophylactic effects on arrhythmia, and very low-dose landiolol might be effective for preventing postoperative atrial fibrillation (POAF) and sinus tachycardia. Likewise, landiolol is an optimal choice for perioperative tachycardia treatment during cardiac surgery. The high β1 selectivity of landiolol is useful in heart failure patients as a first-line therapy for tachycardia and arrhythmia as it avoids the typical depression of cardiac function seen in other β-blockers. Application in cardiac injury after percutaneous coronary intervention (PCI), protection for vital organs (lung, kidney, etc.) during sepsis, and stabilizing hemodynamics in pediatric patients are becoming the new frontier of landiolol use. Conclusion: Landiolol is useful as a first-line therapy for the prevention of POAF after cardiac/non-cardiac surgery, fatal arrhythmias in heart failure patients and during PCI. Moreover, the potential therapeutic effect of landiolol for sepsis in pediatric patients is currently being explored. As positive RCT results continue to be published, new clinical uses and further clinical studies in various settings by cardiologists, intensivists and pediatric cardiologists are being conducted.

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“…Esmolol is the beta-blocker that has been most frequently evaluated in patients with sepsis, as its pharmacokinetic profile allows for rapid titration when used intravenously [ 10 , 27 – 29 , 31 ]. However, landiolol has demonstrated a more favorable pharmacokinetic and pharmacodynamic profile than esmolol [ 52 – 55 ]. Landiolol has a faster onset (1 min vs 2 min) and shorter half-life (4 min vs 9 min) than esmolol, which should allow for more rapid titration and enhanced safety [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Landiolol in patients with septic shock resident in an intensive care unit (LANDI-SEP): study protocol for a randomized controlled trial

Unger

Morelli

Singer

et al. 2018

Trials

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BackgroundIn patients with septic shock, the presence of an elevated heart rate (HR) after fluid resuscitation marks a subgroup of patients with a particularly poor prognosis. Several studies have shown that HR control in this population is safe and can potentially improve outcomes. However, all were conducted in a single-center setting. The aim of this multicenter study is to demonstrate that administration of the highly beta1-selective and ultrashort-acting beta blocker landiolol in patients with septic shock and persistent tachycardia (HR ≥ 95 beats per minute [bpm]) is effective in reducing and maintaining HR without increasing vasopressor requirements.MethodsA phase IV, multicenter, prospective, randomized, open-label, controlled study is being conducted. The study will enroll a total of 200 patients with septic shock as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria and tachycardia (HR ≥ 95 bpm) despite a hemodynamic optimization period of 24–36 h. Patients are randomized (1:1) to receive either standard treatment (according to the Surviving Sepsis Campaign Guidelines 2016) and continuous landiolol infusion to reach a target HR of 80–94 bpm or standard treatment alone. The primary endpoint is HR response (HR 80–94 bpm), the maintenance thereof, and the absence of increased vasopressor requirements during the first 24 h after initiating treatment.DiscussionDespite recent studies, the role of beta blockers in the treatment of patients with septic shock remains unclear. This study will investigate whether HR control using landiolol is safe, feasible, and effective, and further enhance the understanding of beta blockade in patients with septic shock.Trial registrationEU Clinical Trials Register; EudraCT, 2017-002138-22. Registered on 8 August 2017.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-3024-6) contains supplementary material, which is available to authorized users.

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Pharmacokinetics and pharmacodynamics of two different landiolol formulations in a healthy Caucasian group

Cited by 13 publications

References 42 publications

Pharmacodynamic and pharmacokinetic behavior of landiolol during dobutamine challenge in healthy adults

Pharmacodynamic and pharmacokinetic behavior of landiolol during dobutamine challenge in healthy adults

<p>Evaluating the Therapeutic Efficacy and Safety of Landiolol Hydrochloride for Management of Arrhythmia in Critical Settings: Review of the Literature</p>

Landiolol in patients with septic shock resident in an intensive care unit (LANDI-SEP): study protocol for a randomized controlled trial

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