Pharmacokinetics of orally administered melatonin in critically ill patients

Abstract

Critically ill patients exhibit reduced melatonin secretion, both in nocturnal peaks and basal daytime levels. Oral melatonin supplementation may be useful for known sedative and antioxidant properties. Its early enteral absorption and daily pharmacokinetics were determined in two cohorts of six high-risk patients in this prospective trial. During their third and fourth Intensive Care Unit (ICU) day, they underwent two different sets of repeated blood samples to detect serum melatonin levels through radio-immuno-assay. Cohort 1: samples taken at 20:00, 20:45, 21:30, 24:00, 03:00, 06:00, 14:00, 20:00 to describe the daily pharmacokinetics. Cohort 2: 20:00, 20:05, 20:10, 20:20, 20:30, 20:45 to study the early absorption. On ICU day 3, endogenous levels were measured, while the absorption of exogenous melatonin was determined on ICU day 4 after administration, at 20:00, of 3 mg melatonin. All basal levels were below the expected values. Following enteral administration, pharmacological levels were already reached in 5 min, with a serum peak after 16 min (half-absorption time: 3 min 17 s). The maximum serum level observed was 11040 pg/mL and the disappearance rate indicated a half-elimination time of 1 hr 34 min. Serum melatonin levels decreased significantly after midnight; pharmacological levels were maintained up to 10 hr following administration. No excessive sleepiness was reported in this patient group. Critically ill patients exhibited reduced melatonin secretion, as reported in the literature. Despite the critical illness, the oral bioavailability was satisfactory: serum levels after oral administration showed basically unchanged intestinal absorption, while disappearance rate was slower than reported elsewhere in healthy volunteers.

Clinical pharmacokinetics of melatonin: a systematic review

“…Nineteen studies included healthy volunteers [8, 9, 11-15, 17-20, 22-29]. Three clinical studies included critically ill patients [3,16] and elderly patients suffering from insomnia [21], respectively.…”

“…1. Twenty-two studies (n=359) were included in the review [3,8,9,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. Table 1 describes number of volunteers/patients, study design, volunteer/patient characteristics, measuring period, and reported pharmacokinetic variables.…”

“…T max was reported in 17 studies [3,11,[13][14][15][16][17][19][20][21][22][23][24][25][26][27][28]. For intravenous infusions, T max was 113.4 min for male volunteers and 110.4 min for female volunteers (dose 0.023 mg, 250 ml/h), respectively [20].…”

“…The pharmacokinetics of melatonin has been investigated in three studies investigating critically ill patients [3,16] and elderly patients with insomnia [21], respectively.…”

“…C max was measured in 18 studies [3,8,11,13,14,[16][17][18][19][20][21][22][23][25][26][27][28][29]. C max after intravenous bolus administration was 96, 850 pg/ml (dose 2 mg) [8].…”