Melatonin pharmacokinetics following two different oral surge‐sustained release doses in older adults

Abstract

Melatonin is increasingly used for the treatment of sleep disorders. Surge-sustained formulations consisting of combined immediate release and controlled release dosing may mimic the endogenous melatonin physiologic profile. However, relatively little is known about the pharmacokinetic properties of low dose (<0.5 mg) and high dose (>2 mg) melatonin in a combined immediate release/controlled release dose, especially in older adults who may also exhibit altered melatonin disposition. To assess this, we conducted a randomized, double-blind, placebo-controlled study of low (0.4 mg) and high (4.0 mg) dose melatonin (25% immediate release+75% controlled release) in 27 older adults with insomnia complaints and low endogenous melatonin levels to determine if melatonin pharmacokinetic properties differ between these two doses. The time to maximum level (1.3 hrs vs 1.5 hrs), elimination half-life (1.8 hrs vs 2.1 hrs), and apparent total clearance (379 l/hr vs 478 l/hr) did not differ significantly between the low and high dose arms, respectively. The maximum concentration was 405±93 pg/ml for the low dose arm and 3999±700 pg/ml for the high dose arm, both of which are substantially higher than physiologic melatonin levels for this age group. In addition, subjects in the high dose arm maintained melatonin levels >50 pg/ml for an average of 10 hours, which could result in elevated melatonin levels beyond the typical sleep period. Renal and liver function parameters remained stable after 6 weeks of treatment. The linear pharmacokinetic behavior of melatonin observed in the elderly can form the basis for future studies exploring a wider range of dosing scenarios to establish exposure-response relationships for melatonin-mediated sleep outcomes.

Chronomedicine and type 2 diabetes: shining some light on melatonin

“…Similar experiments that apply chronic melatonin treatment to obese individuals, those with impaired glucose tolerance or full type 2 diabetes are necessary to confirm and extend these observations. [136,155]. However, to target the melatonin signalling pathway with greater efficiency, several long-lasting high affinity MT1/MT2 receptor agonists have been developed [155][156][157][158].…”

“…Results from preclinical study of melatonin's effect on glucose homeostasis should be interpreted with caution. For one, the effective dose of melatonin is often exceedingly high (>5 mg/kg) and well above the recommended dosage used for the clinical treatment of sleep disorders (2-4 mg/day; [136]). Further, a caveat to studies in rodents is the obvious species divergence in the timing of melatonin secretion relative to food intake, peak insulin secretion and serum glucose.…”

Clinical pharmacokinetics of melatonin: a systematic review

“…The review included five randomized clinical trials (RCT) [3,8,17,21,28], 16 cohort studies [9, 11-16, 18-20, 22, 23, 25-27, 29], and one case report [24]. Nineteen studies included healthy volunteers [8, 9, 11-15, 17-20, 22-29].…”

“…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.…”

Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders

“…Exogenous melatonin has no reported tolerance, dependence, or 'hangover effect' [11], and no adverse effect on alertness or mood the following day [12], as well as minimal side-effects (e.g., headache, dizziness, nausea, drowsiness) [13,14] if administered at a low dose. [15] Melatonin has a short half-life of only 30-50 minutes and can induce phase shifts in the circadian timing system (both central and peripheral clocks) and when administered acutely, reduces core body temperature and lowers alertness, encouraging sleep propensity. [16] M A N U S C R I P T…”