The Relative Bio-availability of Oral and Oromucosal Melatonin in Different Formulations in Healthy Human Volunteers. A Three-phased Cross-over Study.

The circadian rhythm, the sleep-wake cycle, is mainly regulated by melatonin. The synthesis of melatonin is stimulated by the absence of light, leading to peak serum levels before bedtime. In humans, this endogenous "signaling" neurohormone induces sleep.

Exogenous melatonin can be beneficial in different sleep disturbances including delayed sleep phase insomnia (Dahlitz et al. 1991, Regestein et al. 1995), melatonin- deficiency-related insomnia (especially in elderly) (Garfinkel 1995, Etzioni et al. 1995) and shift work sleep disorder (Folkard et al. 1993, Skene et al. 1996).

A randomized controlled trial of van Geijlswijk et al. (van Geijlswijk 2010) showed that no relationship could be demonstrated between melatonin dose (0.05-0.15 mg/kg) and shift of sleep onset time (SOT), shortening of sleep onset latency (SOL) and shift of dim light melatonin (DLMO). On the other hand, the timing of melatonin administration did have a clinically and statistically significant effect on all three parameters. Timing of melatonin administration in relation to baseline DLMO determines the phase advance, as can be measured by the shift of DLMO and SOT to an earlier time in the evening, resulting also in a shorter SOL. Melatonin must be administered in a closely defined time-slot before endogenous DLMO and before bedtime. The phase advance occurs when melatonin is administered 1-2 hours before DLMO and bedtime (van Geijlswijk et al. 2010). This trial demonstrated that low dosage of melatonin (0.05mg/kg) is effective in children when given at least 1-2 hours before the individual DLMO and the desired bedtime. This means that the release of melatonin from any pharmaceutical formulation should occur fast enough in order to achieve predictive high levels within the desired time-slot before the occurrence of (baseline) DLMO to induce a phase advance. These high maximum serum levels shortly after administration (Tmax) means the release rate of melatonin from the formulation needs to be as fast as possible and the bioavailability needs to be as high as possible.

Melatonin is known for its low and variable bioavailability in humans due to a high first pass effect and variable pharmacokinetics and short half-life. In order to prevent exposure of patients with unnecessary high dosages of melatonin and in order to achieve a short Tmax and high bio-availability of melatonin, a proper formulation needs to be defined. Thereby, the bioavailability must be made less variable in order to understand the biologic effects of melatonin (Di 1997).

Aim/objective. This study, a three-phased cross-over study, aims to define a proper formulation for oral and oromucosal melatonin for the treatment of insomnia by investigating the Tmax and relative bioavailability derived from melatonin levels in salivary samples of healthy volunteers after administration of melatonin in different formulations: 2,5mg melatonin immediate release capsule (produced by Apotheek UMCU), 1mg melatonin immediate release tablet (produced by Tiofarma), low-dose 0.1mg melatonin original Sleepzz tablet (produced by Vemedia Manufacturing BV).