Pharmacokinetics of a novel dosing regimen of oral melatonin in critically ill patients

Judith Bellapart; Jason Alexander Roberts; Vinesh Appadurai; Steven C. Wallis; Maria Nuñez-Nuñez; Robert James Boots

doi:10.1515/cclm-2015-0323

Article

Pharmacokinetics of a novel dosing regimen of oral melatonin in critically ill patients

Judith Bellapart , Jason Alexander Roberts , Vinesh Appadurai , Steven C. Wallis , Maria Nuñez-Nuñez and Robert James Boots

Published/Copyright: September 1, 2015

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From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 54 Issue 3

Abstract

Background: Loss of circadian rhythms and reduced concentrations of endogenous melatonin are common in critically ill patients. After exogenous administration, supra-physiological concentrations in serum are only ephemeral, which may explain the absence of significant therapeutic effect on sleep. The aim of this study is to describe the pharmacokinetics of enteral melatonin in critically ill patients administered in a novel regimen aiming to simulate endogenous release.

Methods: Thirteen patients in the recovery phase of critical illness were randomised to receive enteral melatonin or placebo. In the melatonin group, a total of 6 mg was administered as solution through their feeding tube, commencing with a 3 mg loading dose at 9 pm and six subsequent 0.5 mg doses hourly. The placebo was administered using a similar regimen. Serial blood samples were taken and measured using a validated chromatographic method. The concentration-time data for serum melatonin concentrations were described using non-linear mixed-effects modelling.

Results: The observed concentrations in the melatonin patients were significantly higher than that observed in the placebo patients. The concentrations in the patients administered melatonin were also higher than endogenous melatonin concentrations previously reported in non-critically ill patients. The patients administered melatonin had a mean clearance, volume of distribution and absorption rate constant of melatonin was 55.2 L/h, 767 L and 0.76 h^–1, respectively.

Conclusions: Exogenous administration of melatonin with a loading dose of 3 mg followed by an hourly dose of 0.5 mg demonstrates good oral bioavailability and results in supra-physiological and sustained concentrations of serum melatonin during 12 h overnight.

Keywords: critical illness; drug delivery; melatonin pharmacokinetics

Corresponding author: Dr. Judith Bellapart, Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Butterfield Street, Herston, QLD 4025, Australia, Phone: +61 736368897, Fax: +61 736363542, E-mail: judithbellapart@gmail.com

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: This work was supported by the Royal Brisbane and Women’s Hospital, Research Foundation project grant 2011. Jason Roberts is supported by a Career Development Fellowship from the National Health and Medical Research Council of Australia (APP1048652).

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organisation(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Received: 2015-4-6

Accepted: 2015-7-27

Published Online: 2015-9-1

Published in Print: 2016-3-1

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Articles in the same Issue

https://doi.org/10.1515/cclm-2015-0323

Keywords for this article

critical illness; drug delivery; melatonin pharmacokinetics