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Bolus application of landiolol and esmolol: comparison of the pharmacokinetic and pharmacodynamic profiles in a healthy Caucasian group

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Abstract

Purpose

The aim of this prospective study was to compare in non-Asian subjects the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of two short-acting cardioselective β1-adrenergic antagonists, landiolol and esmolol, after administration of three different bolus dosages.

Materials and methods

We conducted a single-center, prospective, double-blinded, randomized study in three cross-over periods with 12 healthy subjects (7 women and 5 men, mean age of 24.5 ± 6.9 years) each receiving three doses of landiolol (0.1, 0.2, and 0.3 mg/kg BW) either in a newly developed concentrate i.v. formulation (Rapibloc® 20 mg/2 mL concentrate) or a lyophilized formulation, or three doses of esmolol (0.5, 1, and 1.5 mg/kg BW) in an i.v. formulation (Brevibloc® 100 mg/10 mL). PK and PD parameters, safety, and tolerability were assessed.

Findings

Results of the two landiolol formulations were reported previously and were similar. For the landiolol concentrate formulation and esmolol, maximum blood concentrations were rapidly reached (mean t max ranged between 1.8 and 3.0 min for landiolol and 1.8 to 2.4 min for esmolol). The parent drugs disappeared very fast from the blood stream, with a t 1/2 of 3.2 ± 1.2 (SD) minutes and 3.7 ± 2.1 (SD) minutes for the low doses of landiolol and esmolol, respectively. Despite comparable injection rates (0.1 or 0.5 mg/kg/15 s for landiolol and esmolol, respectively), the onset of significant heart rate reduction occurred earlier in response to landiolol (1 min) than in response to esmolol (2 min). In addition, significantly lower heart rate values were obtained at every dose level of landiolol, in comparison to esmolol (p < 0.05). Both compounds reduced the systolic blood pressure to a comparable degree. Especially at the highest dose, the duration of blood pressure reduction was longer under esmolol compared to landiolol. Seven mild to moderate adverse events occurred after administration of landiolol, and five occurred after administration of esmolol. No serious adverse events were reported in this study.

Implications

Heart rate reduction induced by a new liquid formulation of landiolol occurred faster, was more pronounced, and lasted longer than the effects of corresponding standard esmolol doses. Both agents reduced systolic blood pressure to a comparable degree, but the blood pressure decrease lasted longer after esmolol infusion. The local tolerance and safety profiles of the two formulations were similar. In summary, compared to esmolol, landiolol shows a more prominent and pronounced bradycardic effect in relation to its blood pressure-lowering effect, an action profile that might be of specific advantage in the perioperative setting.

Trial registration

NCT01652898 and 2012-002127-14. https://clinicaltrials.gov/ct2/show/NCT01652898?term=landiolol&rank=7

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Authors’ contributions

GK: study conception and design, drafting of manuscript, analysis and interpretation of data; IU: acquisition of data; MT, JH: study conception and design; PK: analysis and interpretation of data.

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Authors and Affiliations

  1. MRN Medical Research Network GmbH, Postgasse 11/22, A-1010, Vienna, Austria

    Günther Krumpl

  2. Center for Pharmacology and Analysis s.r.o, Prague, Czech Republic

    Ivan Ulc

  3. AOP Orphan Pharmaceuticals AG, Wien, Austria

    Michaela Trebs & Juri Hodisch

  4. Aprova s.r.o, Prague, Czech Republic

    Pavla Kadlecová

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  1. Günther Krumpl
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  2. Ivan Ulc
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  3. Michaela Trebs
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  4. Pavla Kadlecová
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  5. Juri Hodisch
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Correspondence to Günther Krumpl.

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This prospective study was performed in a single center in compliance with the study protocol, Declaration of Helsinki, and GCP and GLP guidelines, as well as other applicable international and national regulatory requirements and local laws. The study protocol was approved by an independent ethics committee (ECO 410-12, CEPHA s.r.o., Komenského 19, CZ-323 00 Pilsen, Czech Republic). The study was registered at clinicaltrials.gov (NCT01652898) and EudraCT (2012-002127-14). All study participants gave written informed consent before the conduct of the study-related procedures.

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Krumpl, G., Ulc, I., Trebs, M. et al. Bolus application of landiolol and esmolol: comparison of the pharmacokinetic and pharmacodynamic profiles in a healthy Caucasian group. Eur J Clin Pharmacol 73, 417–428 (2017). https://doi.org/10.1007/s00228-016-2176-0

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