The Relative Bio-availability of Oral and Oromucosal Melatonin in Different Formulations in Healthy Human Volunteers.
Condition: Pharmacokinetics of Melatonin
Study type: Interventional

Summary: 
      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, melatonin- deficiency-related insomnia (especially in elderly) and shift work sleep
      disorder. 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.
      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).
    

Detailed description: 
      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).

      Study-design. Three-phased cross-overstudy. Study-population. The study population will
      consist of 10 healthy volunteers (male) aged 18 to 35 years old without insomnia. They will
      be recruited in the Netherlands. Intervention. The intervention starts between 10:00 and
      11:00 am when the participant flushes his mouth with water, waits 15 minutes and starts to
      chew on a cotton plug during 1 minute. Directly after that the participant will administer
      one of the IMP's according to the instructions. The tablet and capsule will be swallowed. The
      sublingual tablet will be administered sublingual. 10 minutes after administration the
      subjects will drink one glass of water and subsequently try to swallow as much liquid
      (including saliva), in order to prevent contamination of the saliva sample with the remaining
      exogenous melatonin. At 15 minutes, 30 min, 1 hour, 1.5 hour, 2 hours and 3 hours after oral
      administration the participant will chew on new cotton plugs during 1 minute. After
      administration of the sublingual tablet saliva samples will be collected at 25 minutes, 40
      minutes, 60 minutes, 1.5 hour, 2 hours and 3 hours after sublingual administration. 15
      minutes before each sampling the subject will flush his mouth with water. The cotton plugs
      with salivary will be preserved in a test-tube in the freezer and will be analyzed by
      Ziekenhuis Gelderse Vallei.

      Main study endpoint: the Tmax and relative bioavailability of oral and oromucosal melatonin
      derived from melatonin levels in salivary samples of healthy volunteers.

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness:

      This study will burden the participants in a small extent. As mentioned before, melatonin is
      well tolerated and is not reported to have a hangover effect. Its rarely occurring side
      effects include fatigue, dizziness, nausea, mild drowsiness, hypothermia and headache (Wagner
      1998, Waldhauser 1990, Dahlitz 1991, Garfinkel 1995, Dollins 1994). Besides that, the
      participants will be asked to perform simple actions during 3 intervention days for only 3
      hours.

      The low dose 0.1mg melatonin original Sleepzz table is available without prescription in
      drugstores in the Netherlands. The tablet will also contain low dosage of melatonin,
      respectively 1mg and the capsule will contain regular dose of melatonin (2,5mg). These
      dosages are safe for adults and children. A few reports have been published on the
      consequences of long-term treatment with melatonin in humans. (Severe) adverse events were
      not described in these reports. (Van Geijlswijk 2011, Jan et al. 1996, Jan et al. 1994,
      Gilberg et al. 1997, Smits et al. 2001, Arendt 2000).
    

Intervention name(s): Melatonin
Intervention type(s): Drug
Intervention description(s): swallowing 1 piece, collecting saliva afterwards
Other intervention name(s): Melatonin 2,5 mg capsule (compounded by UMCU Pharnacy); Melatonin 1 mg tablet Thiopharma; Sleepzz 0.1 mg oromucosal tablet
Intervention MeSH terms: Melatonin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: melatonin; bioavailability; pharmacokinetics