Objective: To evaluate the influence of age on the pharmacokinetics and pharmacodynamics of single doses of TAK-375, a selective ML-1 receptor agonist currently under evaluation for the treatment of insomnia and circadian rhythm sleep disorders. Design: A randomized, double-blind, single-dose, two-way crossover study. Materials and Methods: Forty-eight healthy subjects participated, divided into 4 groups (n=12 per group): young men and women, aged 18-34 years, and elderly men and women, aged 63-79 years. Subjects received 16 mg of TAK-375 in the morning 90 minutes after a light breakfast, followed by blood sampling during the next 24 hours. Plasma concentrations of TAK-375 and its principal metabolite (M-II) were analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetic parameters for TAK-375 and M-II were determined by model-independent methods. One week later, subjects received 16 mg of TAK-375 or placebo in the morning on two occasions, separated by at least 1 week. Self and observer ratings of sedation and the digit-symbol substitution test (DSST) were done prior to dosing and at multiple time points during the next 24 hours. The word-list test of information acquisition and recall was done at 1 and 24 hours after dosing. Results: For TAK-375, AUC0-inf (area under the serum concentration curve) and Cmax (peak serum concentration) values were significantly greater in elderly subjects compared with young subjects (AUC0-inf = 18.7±19.4 vs 10.5±12.8, P=0.011; Cmax = 11.6±13.8 vs 6.9±7.6 ng/mL, P=0.024). A similar trend was seen with M-II (AUC0-inf = 482.6±143.5 vs 375.9±132.9, P=0.009; Cmax = 124.9±32.0 vs 110.2±29.7 ng/mL, P=0.091). Half-lives of both TAK-375 and M-II were also greater in elderly subjects (T½ for TAK-375 = 2.60±1.14 vs 1.57±0.778 hours, P=0.004; T½ for M-II = 3.21±0.67 vs 2.42±0.57 hours, P<0.001). Urinary excretion of TAK-375 and its metabolites was negligible (~5% of total dose), with no apparent age differences. Area under the 8-hour curve of pharmacodynamic effect (change over baseline) versus time was examined. There were no statistically significant differences between TAK-375 and placebo in young men, young women, or elderly men for measures of observer-rated sedation, self-rated sedation, or DSST scores. The same was true for elderly women on the observer-rated sedation measure. However, TAK-375 was significantly different from placebo (P<0.05) in elderly women for self-rated sedation (increase) and DSST score (increase). There were no differences between TAK-375 and placebo on the test of information acquisition and recall in any of the subject groups. The incidence of adverse events was similar between age groups, with the most common adverse event being somnolence. Conclusion: Elderly subjects, on average, experienced higher systemic exposure of TAK-375 compared to young subjects, although individual variability was high. In young men, young women, and elderly men, TAK-375 16 mg and placebo were not significantly different for measures of observer-rated sedation, self-rated sedation, memory, or DSST scores. For elderly women, there were no significant differences in observer-rated sedation or memory. There was a statistically significant effect of TAK-375 on self-rated sedation and DSST scores in elderly women; however, the differences from placebo were quantitatively small.
Back to PA Monday Poster Sessions
Back to The Eleventh International Congress