Pharmacokinetics of oral melatonin in patients recovering from critical illness

Introduction

The study was designed to evaluate the pharmacokinetics of oral melatonin in patients recovering from critical illness. To re-enforce a patients' circadian rhythm it is necessary to administer an appropriate dose at the correct time. However, data are currently unavailable to guide effective dosing in this population.

Methods

A randomised double-blind placebo controlled trial was performed in 24 critically ill patients weaning from mechanical ventilation. Melatonin 10 mg was administered as an oral solution at 21:00 hours each night for four nights. Pharmacokinetic analysis of plasma melatonin concentrations was undertaken in the first nine patients in the active group. Twelve blood samples were collected from each patient at appropriately spaced intervals. After sample dilution, plasma melatonin was measured in duplicate using a melatonin radioimmunoassay. Plasma concentrations were corrected for endogenous plasma melatonin concentration by subtracting the 21:00-hour baseline value. Pharmacokinetic data from mean values were described using noncompartmental analysis. Nocturnal sleep quantity was measured using the bispectral index (BIS) and expressed as the sleep efficiency index (SEI) and BIS area under the curve (AUC) between 22:00 and 07:00 hours.

Results

Melatonin was rapidly and extensively absorbed with a mean (SD) time to maximum plasma concentration of 0.5 (0) hours, a maximum plasma concentration (C_max) of 14,974 (3,200) pg/ml and the area under the plasma concentration time curve 0–24 hours (AUC_(0–24)) was 29,979 (8,205) ng.hour/l. Plasma concentrations declined biexponentially with an overall plasma half-life of 1.47 (0.28) hours. Clearance of this liver-metabolised drug resembled cirrhotic patients [1] rather than healthy individuals [2]. Both C_max and AUC_(0–24) had a moderately strong correlation with plasma ALT concentrations; r = 0.7 (P = 0.04) and r = 0.62 (P = 0.07), respectively. No such association was found with age, gender, weight, creatinine or bilirubin. Morning plasma levels (plasma concentration at 08:00 hours) remained supraphysiological at 84 (64) pg/ml. No association was found between the pharmacokinetic parameters C_max, AUC_(0–24) or plasma concentration at 08:00 hours and the mean SEI or BIS AUC measurements of nocturnal sleep.

Conclusion

The 10 mg nocturnal dose is excessive in this population, and reduced doses should be used in future chronotherapeutic studies of exogenous melatonin.