Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults

Abstract

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 (<0.5mg) and high-dose (>2mg) 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 (0.4mg) and high-dose (4.0mg) 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 (1.3hrs versus 1.5hrs), elimination half-life (1.8hrs versus 2.1hrs), and apparent total clearance (379L/hr versus 478L/hr) did not differ significantly between the low- and high-dose arms, respectively. The maximum concentration was 405 ±93pg/mL for the low-dose arm and 3999±700pg/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 >50pg/mL for an average of 10hrs, which could result in elevated melatonin levels beyond the typical sleep period. Renal and liver function parameters remained stable after 6wks 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.

Conflict of interest statement

Conflicts of Interest: There are no author conflicts of interest related to this manuscript

© 2011 John Wiley & Sons A/S.

Figures

Figure 1

Baseline endogenous melatonin secretion pattern in elderly subjects. Serum melatonin levels were measured in all subjects pre-treatment for 24 hours. Insert: Serum melatonin levels from six patients who did not exhibit circadian rhythm secretion pattern. Points represent medians and dashed lines represent 25th and 75th percentile.

Figure 2

Melatonin concentration time profiles in treatment groups on day 42. Serum melatonin levels were measured at the end of the study period for 24 hours from noon to noon next day. Graph depicts melatonin levels after ingestion. Points represent mean ± SD.

Figure 3

Box-and-whisker plot of melatonin (A) Cmax and (B) AUC0-∞ for the treatment groups. Pharmacokinetic parameters were derived from noncompartmental analysis based on melatonin serum levels before treatment (baseline) and treatment day 42.

Figure 4

Correlation between PSQI global score and melatonin PK parameters in the treatment groups.

Figure 5

Effects of exogenous melatonin on renal and hepatic functions. (A) Serum creatinine, (B) ALT, and (C) AST levels were measured before (visit 1) and on day 42 (visit 2) of melatonin treatment.