Clinical Safety, Pharmacokinetics, and Pharmacodynamics of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor ABT-384 in Healthy Volunteers and Elderly Adults.
ABT-384 is a potent and selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1), the enzyme that regenerates cortisol in several tissues. Two clinical studies of ABT-384 were undertaken to assess its safety, pharmacokinetics, target engagement, and pharmacologic effects in healthy subjects. Single doses from 1 to 240 mg, and multiple doses from 1 to 100 mg once daily for 7-14 days, were administered to healthy adults. Multiple doses from 10 to 100 mg once daily for 21 days were administered to elderly subjects. A total of 103 subjects received at least 1 dose of ABT-384. A maximum-tolerated dose was not defined in either study. The pharmacokinetic profiles of ABT-384 and its active metabolite support once daily dosing. Analysis of urine cortisol metabolites demonstrated full hepatic HSD-1 inhibition with regimens from 1 mg daily, and confirmed in vitro target selectivity. Pharmacologic effects included increases of adrenocorticotrophic hormone levels, cortisol production and androgen and estradiol levels. ABT-384 has a wide therapeutic index relative to full hepatic target engagement which is relevant for indications such as diabetes and metabolic syndrome. Its therapeutic index for other potential indications such as Alzheimer's disease remains to be established.
AbbVie, North Chicago, IL, USA.
Wei
W
Liu
AbbVie, North Chicago, IL, USA.
David A
DA
Katz
AbbVie, North Chicago, IL, USA.
Charles
C
Locke
AbbVie, North Chicago, IL, USA.
Dan
D
Daszkowski
AbbVie, North Chicago, IL, USA.
Yi
Y
Wang
AbbVie, North Chicago, IL, USA.
Matthew J
MJ
Rieser
AbbVie, North Chicago, IL, USA.
Walid
W
Awni
AbbVie, North Chicago, IL, USA.
Gerard J
GJ
Marek
AbbVie, North Chicago, IL, USA.
Sandeep
S
Dutta
clinical trial; enzyme inhibitor; hydroxysteroid dehydrogenase; pharmacodynamics; pharmacokinetics