MoA, pharmacokinetics and pharmacodynamics

Q6: How is Circadin® metabolised and how long does it stay in the body?
A6: Circadin®’s prolonged-release formulation releases melatonin gradually over 8-10 hours, providing a terminal (apparent) half-life of 3.5–4 hours(Ref. 1). The released melatonin is rapidly metabolised by the liver (half-life 40–50 minutes)(Ref. 1, Ref. 2). The principal metabolite is 6-sulphatoxy-melatonin (6-SMT), which is inactive and accounts for ~80% of the dose excreted in the urine(Ref. 2). Excretion of the metabolites is completed within 12 hours after ingestion(Ref. 1).

Q7: How does Circadin® work compared to other melatonin formulations?
A7: Circadin® is a prolonged-release formulation of melatonin, which circumvents the fast clearance of the hormone by releasing the melatonin over an extended period of time(Ref. 1), thereby mimicking physiological patterns of melatonin secretion. Administration of exogenous melatonin does not affect the endogenous secretion of melatonin(Ref. 3). Other melatonin formulations are immediate-release – meaning that they are rapidly absorbed and metabolised with an elimination half-life of ~60 minutes(Ref. 4) Following oral administration of immediate-release melatonin, peak plasma levels are reached after ~50 minutes(Ref. 4), rapidly falling off again due to the first-pass hepatic metabolism. Immediate-release melatonin is quickly cleared from the circulation.

Q8: Does the use of Circadin® make the body less able to manufacture its own melatonin; i.e., does the natural melatonin system ‘switch off’ and, if so, does it switch back on again when Circadin® treatment is stopped?
A8: Published literature has shown that administration of exogenous melatonin does not affect the endogenous production of melatonin(Ref. 6, Ref. 7, Ref. 3).

Q9: Should melatonin levels be measured prior to treatment with Circadin®?
A9: The age-related decline in melatonin production, that is proposed to contribute to poor sleep quality, is well-documented(Ref. 8). Additionally, it has been demonstrated that elderly insomnia sufferers exhibit lower melatonin levels than elderly people without insomnia(Ref. 9) However, the inter-individual variations in ‘normal’ levels of melatonin are large. Therefore, measurement of melatonin is not considered relevant in clinical practice. Age is a good surrogate marker of melatonin deficiency in the primary insomnia patient population(Ref. 10).

---

References

1. EPAR, Assessment Report for Circadin. Procedure No. EMEA/H/C/695. 2007.

2. Circadin® 2 mg prolonged-release tablets. Summary of product characteristics. 2008.

3. Matsumoto M, Sack RL, Blood ML, Lewy AJ. The amplitude of endogenous melatonin production is not affected by melatonin treatment in humans. J Pineal Res 1997; 22 (1): 42-44.

4. DeMuro RL, Nafziger AN, Blask DE, et al. The absolute bioavailability of oral melatonin. J Clin Pharmacol 2000; 40 (7): 781-784.

5. Laudon M. Characterization of the urinary excretion of the melatonin metabolite, 6-sulphatoxymelatonin in a large sample of insomnia patients and assessment of 6-sulphatoxymelatonin levels in insomnia patients after long-term (6 months) treatment with prolonged release melatonin (2 mg). Report 6-00. March, 2000.

6. Lissoni P, Rovelli F, Pittalis S, et al. Therapy with melatonin does not suppress its endogenous production in healthy volunteers. [Article in Italian] Recenti Prog Med 1999; 90 (2): 84-85.

7. Mallo C, Zaidan R, Faure A, et al. Effects of a four-day nocturnal melatonin treatment on the 24 h plasma melatonin, cortisol and prolactin profiles in humans. Acta Endocrinol (Copenh) 1988; 119 (4): 474-480.

8. Sharma M, Palacios-Bois J, Schwartz G, et al. Circadian rhythms of melatonin and cortisol in aging. Biol Psychiatry 1989; 25 (3): 305-319.

9. Léger D, Laudon M, Zisapel N. Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy. Am J Med 2004; 116 (2): 91-95.

10. EPAR p. 38/52