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.

Figure 1

Continuous dosing study: mean plasma concentration of TAK-683 by treatment cohort on (A) day 1, (B) day 2, (C) and days 14–16. Values represent mean ± SD. , TAK-683 0.01 mg day⁻¹ (Cohort 1). , TAK-683 0.03 mg day⁻¹ (Cohort 2). , TAK-683 0.1 mg day⁻¹ (Cohort 3). , TAK-683 0.3 mg day⁻¹ (Cohort 4). , TAK-683 2.0 mg day⁻¹ (Cohort 5)

Figure 2

Single dose study: mean concentration–time profile (baseline to 72 h) for (A) total plasma testosterone, (B) LH and (C) FSH after administration of TAK-683 (0.01–2.0 mg) or placebo. , placebo. , TAK-683 0.01 mg. , TAK-683 0.03 mg. , TAK-683 0.1 mg. , TAK-683 0.3 mg. , TAK-683 1.0 mg. , TAK-683 2.0 mg

Figure 3

Continuous dosing study: mean serum concentrations of total testosterone with TAK-683 dosing by treatment cohort on days 1–4, 13 and 14. TAK-683 dose (mg kg⁻¹). , 0.01 mg kg^–1. , 0.03 mg kg^–1. , 0.10 mg kg^–1. , 0.30 mg kg^–1. , 2.00 mg kg^–1

Figure 4

Continuous-dosing study testosterone concentration vs. TAK-683 plasma concentration on day 14, for subjects in cohorts 1 to 5; data are testosterone concentrations for all day 14 samples for all active subjects. •, 0.01 mg day⁻¹. ◯, 0.03 mg day⁻¹. ▾, 0.1 mg day⁻¹. △, 0.3 mg day⁻¹. ▪, 2.0 mg day⁻¹