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

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.

Pharmacodynamics of once- versus twice-daily dosing of nebulized amikacin in an in vitro Hollow-Fiber Infection Model against 3 clinical isolates of Pseudomonas aeruginosa.

This study aims to compare the bacterial killing of once- versus twice-daily nebulized amikacin against Pseudomonas aeruginosa and to determine the optimal duration of therapy. Three clinical P. aeruginosa isolates (amikacin MICs 2, 8, and 64 mg/L) were exposed to simulated epithelial lining fluid exposures of nebulized amikacin with dosing regimens of 400 mg and 800 mg once- or twice-daily up to 7-days using the in vitro hollow-fiber infection model. Quantitative cultures were performed. Simulated amikacin dosing regimens of 400 mg twice-daily and 800 mg once-daily achieved ≥2-log reduction in the bacterial burden within the first 24-hours of therapy for all isolates tested. No dosing regimen suppressed the emergence of amikacin resistance. No difference in bacterial killing or regrowth was observed between 3- and 7-days of amikacin. Amikacin doses of 800 mg once-daily for up to 3-days may be considered for future clinical trials.