Quantification of the effect of AZD5213 on sleep in subjects with Alzheimer’s disease or mild cognitive impairment using a two state Markov model
Oliver Ackaert (1), Tamara van Steeg (1), Kristin Hannesdottir (2), Robert Alexander (2), Karen Raudibaugh (2), Alan Kugler (2), Peter Vis (1)
(1) LAP&P Consultants, (2) AstraZeneca, R&D, Neuroscience iMed
Objectives: H3 antagonists have been extensively investigated for the (symptomatic) treatment of cognitive disorders, such as Alzheimer’s disease (AD) or mild cognitive impairment (MCI). H3 antagonists are effective across multiple cognitive domains (attention, memory) in preclinical studies at high receptor occupancy. However, administration of this class of drug in man is often accompanied by alterations in sleep patterns. This may be the result of enhanced histamine release during prolonged H3 receptor occupancy (extending into the night). Therefore, in a Phase IIa study in patients with mild AD and MCI the effect of AZD5213, a novel and highly selective histamine H3 antagonist, on sleep was quantified.
Methods: 81 subjects with mild AD or MCI were randomized in this double-blind, parallel group, placebo-controlled study of 4 weeks of treatment of three different doses of AZD5213. Repeated, nightly polysomnography (PSG) assessments were conducted at baseline, Week 2 and Week 4. During the PSG the sleep state per 30 second epoch was reported. This highly correlated longitudinal data was analyzed using a Markov modeling approach, in which two states were considered, WAKE and SLEEP with the latter obtained by merging the states REM, Sleep Stages 1, 2, 3 and 4.[1] It was investigated if placebo and/or modeled AZD5213 concentration influenced the intensity of acquisition (u) and clearance of sleep (v).
Results: Both u and v changed over time with a change in the ratio between the two intensities over time. No placebo effect was identified, while the drug concentration decreased u and v according to a sigmoid Emax and a log-linear relationship, respectively. AZD5213 plasma concentrations inhibited transitions to sleep more markedly than transitions to wakefulness. Simulations for various doses (low to high) at steady state (Week 2 and 4) demonstrated that overall time awake increased with increasing dose with a maximum effect at doses above medium strength.
Conclusions: The developed two-state Markov model adequately described and predicted the sleep pattern following QD administration of placebo and AZD5213 at the different occasions. Simulations showed a dose-related increase in the total time awake during the night and increased wakefulness appeared to be associated with receptor occupancies above 70% during the entire night.[2]
References:
[1] Diack C. et al. A hidden Markov model to assess drug-induced sleep fragmentation in the telemetered rat. Journal of Pharmacokinetics and Pharmacodynamics, 38(6):697–711, 2011. [2] Jucaite A. et al. AZD5213: a novel histamine H3 receptor antagonist permitting high daytime and low nocturnal H3 receptor occupancy, a PET study in human subjects. International Journal of Neuropsychopharmacology, 16(6):1231–1239, 2013.
