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The Clinical Pharmacokinetics of L u AA 21004 and its Major Metabolite in Healthy Young Volunteers
Author(s) -
Areberg Johan,
Søgaard Birgitte,
Højer AstridMaria
Publication year - 2012
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2012.00886.x
Subject(s) - pharmacokinetics , metabolite , bioavailability , volume of distribution , dosing , urine , pharmacology , oral administration , chemistry , absorption (acoustics) , medicine , physics , acoustics
L u AA 21004 is a novel multimodal antidepressant that is currently in phase 3 development. The objective of this report was to detail the clinical pharmacokinetics of L u AA 21004 and its major but inactive metabolite L u AA 34443 (3‐methyl‐4‐(2‐piperazine‐1‐yl‐phenylsulfanyl)‐benzoic acid) in healthy men and women aged between 18 and 53 years. Data from two single‐dose and one multiple‐dose study were combined; the total number of volunteers was 97 (64 men, 33 women). Blood and urine samples were collected after p.o. and i.v. administrations to determine the content of L u AA 21004 and Lu AA 34443 performed with a validated method. Standard pharmacokinetic parameters were estimated with non‐compartmental analysis. The absolute bioavailability was 75%. After oral administration, L u AA 21004 showed an extended absorption phase, a medium clearance and a large volume of distribution resulting in late t max values and a mean elimination half‐life of 57 hr. The exposure of L u AA 21004 showed a linear relationship with dose in the dose ranges studied (up to 75‐mg single dosing and 60‐mg multiple dosing). After weight correction, no differences in exposure for L u AA 21004 and L u AA 34443 were observed between men and women. The renal clearance of L u AA 21004 was negligible. The major metabolite L u AA 34443 had a half‐life similar to that of Lu AA 21004 but a lower accumulation ratio at steady‐state, indicating formation‐rate‐limited elimination. In conclusion, L u AA 21004 showed an extended absorption phase, a medium clearance and a large volume of distribution.