Dose assessment of melatonin in sepsis (DAMSEL2) study: Pharmacokinetics of two doses of oral melatonin in patients with sepsis

Abstract

Sepsis is defined as a dysregulated host response to infection, and high-dose melatonin has been proposed as a treatment due to its antioxidant and antiinflammatory properties. However, there are no data describing the pharmacokinetics of high-dose oral melatonin in critically ill patients. We undertook an open-label trial to determine the tolerance of melatonin administration in these patients and pharmacokinetic analysis, to inform a planned randomised controlled trial. Two cohorts of critically ill patients with sepsis due to community-acquired pneumonia received either 20 or 50 mg oral melatonin liquid as a single dose. Blood samples and clinical measures were analysed over the next 24 h. Melatonin was well tolerated and there were no adverse events. Pharmacokinetic modelling showed that a semiphysiological model, which incorporates saturable first-pass hepatic extraction, was a good fit for our data.Maximum levels of melatonin were extremely high in patients receiving the 50 mg dose and levels of the major metabolite were much lower than expected and not different from those seen after 20 mg, suggesting saturation at the higher dose. We conclude that 20 mg seems a suitable dose of liquid melatonin in patients with sepsis.

Melatonin treatment has consistent but transient beneficial effects on sleep measures and pain in patients with severe chronic pain: the DREAM–CP randomised controlled trial

“…Melatonin given in capsules is very rapidly cleared from the circulation. 29 Circadin™ is a prolonged-release formulation of melatonin designed to mimic endogenous secretion, and we used the dose licensed for treating primary insomnia (2 mg). We have showed previously that larger doses of Circadin™ result in prolonged elevation of melatonin concentration which may impact on daytime activities.…”

Potential Neuroprotective Role of Melatonin in Sepsis-Associated Encephalopathy Due to Its Scavenging and Anti-Oxidative Properties

“…Clinical observation led to the conclusion that therapy with melatonin did not lead to any adverse event and was well tolerated. Twenty mg daily was found to be the optimal dose from a pharmacological point of view [ 117 ].…”

Circadian regulation of the immune-hematopoietic system

“…However, it has been our report in the 1980s that first demonstrated that melatonin may directly modulate the immune response [72]. Today, the immunoregulatory role of melatonin is widely recognized to the extent that the indoleamine or its agonists have been proposed for the treatment of viral, bacterial, and parasitic infections as well as autoimmune disorders [73][74][75]. Most interesting, it has been reported that melatonin may be of therapeutic value in sepsis and in coronavirus disease 2019 (COVID-19) [76][77][78].…”