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

ABSTRACT: Introduction:Pyroglutamate-amyloid-? (pE-A?) peptides are major components of A?-oligomers and A?-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-A? peptides. Methods:A 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. Results:PQ912 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. Discussion:This first-in-man study of a compound-targeting QC inhibition justifies further development of PQ912 for the treatment of AD.

SUBMITTER: Lues I

PROVIDER: S-EPMC5975062 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Lues Inge I Weber Frank F Meyer Antje A Bühring Uli U Hoffmann Torsten T Kühn-Wache Kerstin K Manhart Susanne S Heiser Ulrich U Pokorny Rolf R Chiesa Joseph J Glund Konrad K

Alzheimer's & dementia (New York, N. Y.) 20151003 3

<h4>Introduction</h4>Pyroglutamate-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.<h4>Methods</h4>A randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study investigated the safety, pharmacokinetics, and pharmacodynamics of PQ912 in health ...[more]

PMID: 29854937

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Dataset Information

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

Publications

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

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