Pupillography as a sensitive, noninvasive biomarker in healthy volunteers: first-in-man study of BAY 63-9044, a new 5-HT1A-receptor agonist with dopamine agonistic properties.
OBJECTIVE
BAY 63-9044 is a new full 5-HT(1A)-agonist with functional dopamine agonist properties aimed for the treatment of Parkinson's disease. This first-in-man study investigated the pharmacodynamics, safety and tolerability as well as the pharmacokinetics of BAY 63-9044 in a randomized, single-blind, placebo-controlled group-comparison dose escalation study.


METHODS
45 healthy men received BAY 63-9044 as an oral solution in single doses of 0.25 mg, 0.5 mg, 1.2 mg, 2.5 mg and 5.0 mg. Pupil reaction (baseline pupil diameter (DIAM), constriction amplitude (CA)), body temperature, electroencephalography (EEG) and prolactin, cortisol and adrenocorticotrophic hormone (ACTH) served as pharmacodynamic measures and were monitored up to 24 h after drug intake. Safety, tolerability and plasma samples for determination of BAY 63-9044 were followed up to 72 h.


RESULTS
Up to a dose of 2.5 mg, BAY 63-9044 was safe and well tolerated. Dose-limiting adverse events (nausea, vomiting, and dizziness) occurred in 5 out of 6 volunteers at the 5 mg dose. Adverse events resolved spontaneously in all but one volunteers who was treated with an antihistaminergic for vomiting. Dose-dependent changes of DIAM and CA were observed at doses higher than 0.5 mg and 1.2 mg, respectively. Body temperature showed a trend for reduction starting at C(max) in the highest two doses only. No clear effect was found on prolactin, cortisol and ACTH levels. The pharmacokinetics of BAY 63-9044 showed a dose-dependent increase with maximum plasma concentrations reached within 1 h. Plasma concentrations declined in a bi-phased manner with an apparent terminal half-life of 5.2-8.1 h.


CONCLUSIONS
Up to the maximum tolerated dose (MTD) of 2.5 mg BAY 63-9044 was safe and well tolerated and showed predictable linear pharmacokinetics. Pupil reaction may serve as a non-invasive biomarker for pharmacodynamic effects of 5-HT(1A)-compounds with DIAM being the most sensitive parameter.
Wensing
Georg
G
Bayer Healthcare, Clinical Pharmacology, Aprather Weg 18a, 42113 Wuppertal, Germany. georg.wensing@bayerhealthcare.com
Haase
Claus
C
Brendel
Erich
E
Böttcher
Michael Friedrich
MF
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D015415:Biomarkers / Q000378:metabolism; D018491:Dopamine Agonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D011680:Pupil / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013844:Thiazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
C513036:BAY 639044; D015415:Biomarkers; D018491:Dopamine Agonists; D017366:Serotonin Receptor Agonists; D013844:Thiazoles