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

Abstract

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.

Blood Pressure Recovery After Dobutamine Antagonism: Partial With Landiolol, None With Esmolol

“…The pharmacokinetic results and individual PD results have already been published separately. 26,27 One key finding was that the elimination of esmolol, and less so of landiolol, is accelerated in the presence of dobutamine, which has a marked effect on steady-state concentrations. This report focuses on the PD differences between the 2 drugs.…”

“…The pharmacokinetic results obtained in this study have been published elsewhere. 26,27 A key finding was the fact that the pharmacokinetics of both β-blockers are affected in the presence of dobutamine, which results in a marked reduction of steady-state concentrations. The steady-state concentrations of esmolol and landiolol in the presence of dobutamine are ≈120 ng/mL and ≈160 ng/mL, respectively, whereas in an earlier head-to-head comparison between esmolol and landiolol under similar conditions but without dobutamine, the steady-state concentrations had been ≈200 ng/mL for both drugs.…”

Dobutamine Alters the Pharmacokinetic and Pharmacodynamic Behavior of Esmolol

“…This speeded up the elimination of esmolol. Dobutamine does not necessarily increase the elimination of short-acting β-blockers, as landiolol showed no or only a minimal decrease in half-life when administered on top of dobutamine [ 22 ]. As landiolol has a substantially lower distribution volume than esmolol [ 8 ], this discrepancy can be explained easily.…”

“…In our prospective cross-over study in healthy Caucasian volunteers, we investigated the pharmacokinetic and pharmacodynamic characteristics of a permanent infusion of esmolol or landiolol during dobutamine challenge. We describe for the first time the pharmacodynamic and pharmacokinetic behavior of esmolol at the lowest recommended standard dose (50 µg/kg/min) during dobutamine challenge; the results obtained with landiolol are presented separately [ 22 ].…”

Altered spontaneous brain activity during dobutamine challenge in healthy young adults: A resting-state functional magnetic resonance imaging study

“…Tachycardia effects can occur after infusion rates above 2.5 µg/kg/min, possibly resulting in a marked increase in heart rate or blood pressure, especially systolic blood pressure. About 10% of patients in clinical studies had an increase in heart rate of 30 beats per minute or more, and about 7.5% had an increase in systolic blood pressure of 50 mmHg or more (Dubin et al, 2017;Krumpl et al, 2020).…”