Double-blind, randomized, placebo-controlled study of safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-683, an investigational metastin analogue in healthy men.
OBJECTIVE
Two randomized, double-blind, placebo-controlled studies were performed to characterize the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the investigational metastin analogue, TAK-683, in healthy men.


METHODS
We first investigated a single subcutaneous (s.c.) dose of TAK-683 (0.01-2.0 mg) in 60 subjects (TAK-683, n = 42; placebo, n = 18). We then assessed a single s.c. bolus of 0.03-1.0 mg TAK-683 on day 1, followed by a 0.01-2.0 mg day(-1) continuous infusion on days 2-13, to simulate a depot formulation, in 30 subjects (TAK-683, n = 25; placebo, n = 5) for 14 days.


RESULTS
TAK-683 was well tolerated up to a dose of 2.0 mg day(-1) by continuous s.c. infusion for 14 days. Adverse events were similar between TAK-683 and placebo subjects at all dose levels. TAK-683 plasma concentrations generally increased in proportion to dose with single and continuous dosing, with steady-state concentrations achieved by day 2 of continuous dosing. TAK-683 at 2.0 mg day(-1) suppressed testosterone below castration level (<50 ng dl(-1)) in four of five subjects by day 7 of continuous dosing. Luteinizing hormone and follicle stimulating hormone concentrations were suppressed with TAK-683 continuous dosing compared with placebo by up to 70 and 43%, respectively, but this was not consistently dose-dependent.


CONCLUSIONS
In healthy men, s.c. administration of TAK-683 was well tolerated at all dose levels. The PK profile of TAK-683 was favourable, and TAK-683 suppressed testosterone profoundly during continuous dosing. Further investigation of metastin analogues is warranted for the treatment of castration-resistant prostate cancer.
Takeda Global Research & Development Centre (Europe) Ltd, London, UK. g.scott@tgrd.com
Graham
G
Scott
Irfan
I
Ahmad
Katy
K
Howard
David
D
MacLean
Cristina
C
Oliva
Steve
S
Warrington
Darren
D
Wilbraham
Paul
P
Worthington
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007279:Injections, Subcutaneous; D059648:Kisspeptins / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D013739:Testosterone / Q000097:blood
D000970:Antineoplastic Agents; D059648:Kisspeptins; C578072:TAK-683; D013739:Testosterone