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Double-blind, randomized, placebo-controlled study of safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-683, an investigational metastin analogue in healthy men.

ABSTRACT: AIMS: 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.

SUBMITTER: Scott G

PROVIDER: S-EPMC3579253 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Double-blind, randomized, placebo-controlled study of safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-683, an investigational metastin analogue in healthy men.

Scott Graham G Ahmad Irfan I Howard Katy K MacLean David D Oliva Cristina C Warrington Steve S Wilbraham Darren D Worthington Paul P

British journal of clinical pharmacology 20130201 2

<h4>Aims</h4>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.<h4>Methods</h4>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) continu ...[more]

PMID: 22803642

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Project description:BACKGROUND:Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor kappa-B ligand, a cytokine essential for the formation, function and survival of osteoclasts. This study assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of single-dose denosumab (60 and 120 mg) in healthy Chinese volunteers. METHODS:This randomized (3:3:2), single-blind, placebo-controlled study enrolled healthy Chinese volunteers to receive single subcutaneous injection of denosumab 60 mg, 120 mg, or placebo. Study consisted of screening period (up to 21 days), treatment and assessment period (19 weeks), and an end-of-study visit (at week 26). Denosumab pharmacokinetics and pharmacodynamics parameters were estimated using non-compartmental analysis. Safety and tolerability were assessed throughout the study. RESULTS:A total of 63 volunteers received the study treatment and 62 (98.4%) completed the study. Denosumab serum concentrations peaked at around Day 10 with dose-proportional increase from 60 mg to 120 mg. The mean terminal half-life of denosumab 60 mg and 120 mg was 15 days and 26 days, respectively. The serum C-terminal cross-linking telopeptide of type I collagen concentration-time profiles were similar (>80% decrease within 5 days) between denosumab 60 mg and 120 mg groups. The most commonly reported adverse event (AE) was decreased blood calcium levels (denosumab 60 mg, n = 13; denosumab 120 mg, n = 13; placebo, n = 1); however only one volunteer had calcium level below the abnormality value of potential clinical importance and none of the volunteers developed symptoms of hypocalcemia. The majority of AEs were of mild to moderate intensity. There were no deaths, serious AEs, or withdrawal from study due to AEs. No clinically significant findings in vital signs or electrocardiogram were observed. CONCLUSIONS:Both denosumab 60 mg and 120 mg were well tolerated with no new safety concerns identified in healthy Chinese volunteers with similar pharmacokinetics and pharmacodynamics profiles to that of Caucasians. TRIAL REGISTRATION:ClinicalTrial.gov NCT02135640.

Dataset Information

Double-blind, randomized, placebo-controlled study of safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-683, an investigational metastin analogue in healthy men.

Publications

Double-blind, randomized, placebo-controlled study of safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-683, an investigational metastin analogue in healthy men.

Similar Datasets

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