Population pharmacokinetics of intranasally administered low dose melatonin

Melatonin is an endogenous hormone secreted by the pineal gland and plays a role in the regulation of the circadian rhythms, sleep and mood. Several studies evaluated the use of oral melatonin in sleep disorders, jet lag and shift work. No side‐effects have been reported in these trials [1]. However, it is known that oral melatonin shows poor bioavailability, either due to poor absorption, large first‐pass metabolism or both [2]. Other routes of administration, in particular nasal, have been described [3]. Eight healthy male volunteers (mean age 25 years) received, in an open randomized cross‐over fashion, placebo and intranasal melatonin 200 and 400 µg. Blood was sampled 15 times during 8 h. The study was approved by the Ethics Committee. Melatonin was determined by r.i.a. Plasma melatonin concentrations were adjusted for the mean endogenous concentration after placebo. We calculated the pharmacokinetic parameters of intranasal melatonin by using the MW\Pharm programme [4] according to the ITSB method. The AUC(0, 8 h) was obtained by the trapezoidal rule. The model was validated by Monte Carlo simulation. Melatonin intranasal kinetics could best be described by a 2‐compartment model ( Table 1). Melatonin 200 and 400 µg provided high blood plasma concentrations after fast absorption. The elimination half‐life of melatonin was 44±7 min and 60±20 min after dosing respectively 200 and 400 µg ( P >0.05). Absorption was too rapid to be fitted. Monte Carlo analysis showed that data differed significantly ( P <0.05) from the fitted population parameters. 1 Pharmacokinetic parameters after intranasal administration of 200 and 400 µg melatonin.Parameters 200 µg ( n =7) 95% CI Median±d.f. Median±s.d.AUC(0, 8 h)&!emsp;(µg l −1  h) 2.99±1.16 2.06, 3.92Vd / F (l kg −1 LBMc) 1.41±0.28 1.11, 1.67kel (h −1 ) 1.04±0.14 0.91, 1.16k12 (h −1 ) 0.10±0.12 −0.01, 0.22k21 (h −1 ) 0.05±0.04 0.01, 0.09400 µg ( n =8)ParametersMedian±d.f.Median±s.d.95% CIAUC(0, 8 h)(µg l −1  h) 5.98±2.23 4.12, 7.84Vd / F (l kg −1  LBMc) 1.61±0.69 1.04, 2.18kel (h −1 ) 0.75±0.22 0.57, 0.93k12 (h −1 ) 0.19±0.08 0.13, 0.25k21 (h −1 ) 0.02±0.01 0.01, 0.03AUC: area under the curve, F : absolute bioavailability, V d / F : volume of distribution, k el : elimination rate constant, k 12 , k 21 : rate constants between compartments.The pharmacokinetic parameters could not be validated by a Monte Carlo simulation probably due to large interindividual variability. Because the dose adjusted AUC(0, 8 h) for the 400 µg nasal dose was equal to the AUC(0, 8 h) for the 200 µg nasal dose ( P <0.05), there appears to be linear absorption in the 200 to 400 µg dose range.