A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects

Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 1 - Trang 182-195 - 2015
Inge Lues1, Frank Weber1, Antje Meyer1, Uli Bühring1, Torsten Hoffmann1, Kerstin Kühn-Wache1, Susanne Manhart1, Ulrich Heiser1, Rolf Pokorny2, Joseph Chiesa3, Konrad Glund1
1Probiodrug AG, Halle (Saale), Germany
2Covance Clinical Research Unit AG, Allschwil (Basel), Switzerland
3Covance Clinical Research Unit Ltd, Leeds, UK

Tóm tắt

AbstractIntroductionPyroglutamate‐amyloid‐β (pE‐Aβ) peptides are major components of Aβ‐oligomers and Aβ‐plaques, which are regarded as key culprits of Alzheimer's disease (AD) pathology. PQ912 is a competitive inhibitor of the enzyme glutaminyl cyclase (QC), essential for the formation of pE‐Aβ peptides.MethodsA randomized, double‐blind, placebo‐controlled, single‐ and multiple‐ascending oral dose study investigated the safety, pharmacokinetics, and pharmacodynamics of PQ912 in healthy nonelderly and elderly subjects.ResultsPQ912 was considered safe and well tolerated with dose‐proportional pharmacokinetics up to doses of 200 mg. At higher doses up to 1800 mg, exposure was supraproportional and exposure in elderly subjects was approximately 1.5‐ to 2.1‐fold higher. Exposure in cerebrospinal fluid (CSF) was approximately 20% of the unbound drug in plasma, and both serum and CSF QC activity was inhibited in a dose‐related manner.DiscussionThis first‐in‐man study of a compound‐targeting QC inhibition justifies further development of PQ912 for the treatment of AD.

Tài liệu tham khảo

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Alzheimer's and Dementia: Translational Research and Clinical Interventions

Tập 1

182-195

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