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P4–427: P‐glycoprotein (P‐gp) efflux limits brain penetration of pioglitazone and stereoisomer of pioglitazone is a better brain penetrant
Author(s) -
Chang Kai Lun,
Ho Paul C.
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.08.260
Subject(s) - pioglitazone , pharmacology , chemistry , efflux , pharmacokinetics , high performance liquid chromatography , blood–brain barrier , penetration (warfare) , transporter , rosiglitazone , p glycoprotein , chromatography , medicine , receptor , endocrinology , biochemistry , central nervous system , antibiotics , operations research , multiple drug resistance , type 2 diabetes , engineering , gene , diabetes mellitus
were randomized in this double-blind, parallel group, placebo-controlled study of 4 weeks of treatment of three different doses of AZD5213 or placebo. Repeated, nightly polysomnography assessments were conducted at baseline, Week 2 and Week 4, with clinical and cognitive assessments performed each day following a sleep assessment. Results: AZD5213 was found to be generally safe and well tolerated. There were no drugor dose-related clinically relevant changes or trends in clinical laboratory tests, vital signs, ECGs, or physical examination findings. No sleep-related adverse events were noted in the lowest AZD5213 treatment group. However, a dose-related increase in sleep-related adverse events was noted in the two higher AZD5213 dosage groups. Total sleep time (TST) was not affected in subjects receiving the lowest AZD5213 dose. In contrast, TSTwas reduced in subjects receiving the two higher doses of AZD5213, compared with placebo. Model based analysis indicated that AZD5213 plasma concentrations inhibited transitions to sleep more markedly than transitions to wakefulness. Decrease in TST did not result in next day impairment, as measured by the Psychomotor Vigilance Task and subjective reports of daytime sleepiness. AZD5213 effects on attention/response speed (measured by the CogState IDN task) and memory accuracy (CogState OCL task) were generally small and not clinically relevant. There were no other safety related findings for AZD5213 in this study. Conclusions: AZD5213 was found to be generally safe and well tolerated in subjects with MCI and mild AD. A dose-related increase in sleep-related adverse events, and a dose-related decrease in TST were noted, however, next-day impairment was not observed.