TAK‐906, a Novel D2/D3 Receptor Antagonist: First‐in‐Human Study of Single and Multiple Ascending Doses

Abstract

IntroductionTAK‐906 (previously designated as ATC‐1906M, [3‐((1‐cyclohexyl‐4‐oxo‐8‐(4‐oxo‐4‐phenylbutyl)‐1,3,8‐triazaspiro[4.5]decan‐3‐yl)methyl)benzoic acid. maleate]) is in development for the symptomatic treatment of gastroparesis. TAK‐906 is designed to retain the dopamine receptor antagonist profile and minimal central nervous system (CNS) penetration of domperidone whilst avoiding the cardiac effects. This study aimed to evaluate the pharmacokinetics, pharmacodynamics and safety of single and multiple ascending doses of TAK‐906 in healthy adults.MethodsThis Phase 1, randomized, double‐blind, placebo‐controlled, 2‐phase study was conducted in 72 healthy male and female subjects. In the single‐ascending dose (SAD) phase, TAK‐906 or placebo was administered orally, in the fasted state, to cohorts of 8 subjects each at doses of 5, 10, 25, 50, 100, 200, or 300 mg. Subjects in the 25‐mg cohort received a second 25‐mg dose in the fed state. In the multiple‐ascending dose (MAD) phase, TAK‐906 was administered orally to successive cohorts of 8 subjects each at 50 or 100 mg twice daily (BID) for 4 days with a single dose on Day 5.Results and ConclusionsPharmacokineticsTAK‐906 was rapidly absorbed (median plasma TAK‐906 Tmax ~1.1 hours across all cohorts) and rapidly eliminated (mean plasma TAK‐906 t1/2 ~4.0 hours [SAD cohorts], and 11.0 and 6.2 hours at the 50‐ and 100‐mg BID doses, respectively, on Day 5 [MAD cohorts]). Elimination was monophasic over the first 12 hours after dosing. With single oral doses, TAK‐906 exposure increased proportional to dose (mean Cmax ~2 ng/mL [5‐mg dose] and ~190 ng/mL [300‐mg dose]); CL/F, Vz/F, and t1/2 were not dose dependent. Accumulation was minor with BID dosing for 5 days (<40% for Cmax; <30% for AUC0–12). Food significantly reduced exposure to TAK‐906 25 mg.PharmacodynamicsSerum prolactin concentration, a biomarker for D2 antagonism, increased substantially following administration of single doses of TAK‐906 compared to placebo; the increase was rapid (median Tmax ~0.7 to 1.1 hours) and short‐lived (mean t1/2 10.82 hours). Serum prolactin concentration did not increase in proportion to dose; the prolactin response was maximal at the single 10‐mg dose level (mean TAK‐906 Cmax ~6 ng/mL), with little accumulation with BID dosing for 5 days.Cardiac SafetySingle doses of TAK‐906 between 5 and 300 mg, resulting in plasma concentrations of up to 170 ng/mL, did not have a clinically meaningful effect on placebo‐corrected change from baseline corrected QT interval using Frederica’s method (QTcF).SafetyMonitoring of adverse events, vital signs, clinical laboratory evaluations, CNS and general physical examinations indicated that oral administration of single or multiple doses of TAK‐906 was well tolerated in healthy male and female subjects.Support or Funding InformationThis study was sponsored by Altos Therapeutics, LLC. Formatting and editing support were provided by Oxford PharmaGenesis, Oxford, UK and funded by Takeda Pharmaceutical Company Ltd