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-dose (0.4 mg) and high-dose (4.0 mg) melatonin (25% immediate release + 75% controlled release) in 27 older adults with insomnia complaints and low endogenous melatonin levels to determine whether melatonin pharmacokinetic properties differ between these two doses. The time to maximum level (1.3 hrs versus 1.5 hrs), elimination half-life (1.8 hrs versus 2.1 hrs), and apparent total clearance (379 L/hr versus 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 hrs, which could result in elevated melatonin levels beyond the typical sleep period. Renal and liver function parameters remained stable after 6 wks 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.
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