TAK‐906, a Dopamine D2/D3 Receptor Antagonist with Minimal Brain Penetration for Gastrointestinal Disorders
Authors: Jasper Jeffrey R , Whiting Roger L 
Published: April 2020

IntroductionMetoclopramide and domperidone are dopamine receptor antagonists utilized for the symptomatic treatment of gastrointestinal disorders such as gastroparesis. Metoclopramide is labeled only for acute use due to the potential for extrapyramidal side‐effects elicited through the blockade of central dopamine D2 receptors, while domperidone is a peripherally selective antagonist but therapy is limited due to the potential for cardiac arrhythmias. TAK‐906 is a dopamine receptor antagonist with minimal CNS penetration and minimal potential for cardiac QTc prolongation/arrhythmia.Methods and ResultsThese studies examined the concentration of TAK‐906 in the cerebral spinal fluid (CSF) compared to plasma in rat or dog.
Rat: Concentrations of TAK‐906 in plasma and CSF were assessed in five male and five female Sprague Dawley rats dosed daily via PO gavage for four consecutive days. TAK‐906 was in 5% (v/v) DMSO, 40% (v/v) PEG 400 and 55% (v/v) 0.9% sodium chloride for injection. Blood was collected from jugular vein via syringe on Study Days 1 and 3 at predose and at 1, 6 and 24 hours (hrs) post‐dose. On Study Day 4, blood was collected via cardiac puncture. CSF was collected from the cisterna magna of each animal via syringe. TAK‐906 was detected in CSF samples in limited concentrations relative to concurrent plasma concentrations. The ratio of mean plasma to mean CSF concentrations of TAK‐906 at 1 hr post dose on Day 4 in male or female rats was ~700:1. Prior in vitro studies demonstrated ~90% plasma protein binding of TAK‐906 in rat plasma. Assuming 90% plasma protein binding and zero protein binding in CSF, the ratio of plasma to CSF concentrations of free TAK‐906 was ~70:1 or 98.6% in plasma and 1.4% in CSF.
Dog: Five male and five female non‐naïve beagles were administered TAK‐906 as five oral capsules daily for four consecutive days at 50 mg/kg. Blood was collected from a jugular vein on Study Days 1 and 3 at predose and at 1, 6 and 24 hrs and on Study Day 4 at 1 and 3 hrs post dose. For CSF determination, animals were anesthetized, and CSF was collected from the cisterna magna of each animal via syringe and needle at 1 and 3 hrs post dose on Day 4. TAK‐906 was rapidly absorbed following single and repeat PO dose administration to dogs, with high plasma concentrations observed. TAK‐906 CSF concentrations on Day 4 (1 and 3 hrs post dose) was measurable at concentrations that ranged from 1.35–9.79 ng/mL. The ratio of mean plasma to mean CSF concentrations of total TAK‐906 at 1 hr post dose on Day 4 was ~700:1. Prior in vitro studies demonstrated ~90% plasma protein binding of TAK‐906 in dog plasma. Assuming 90% plasma protein binding and zero protein binding in CSF, the ratio of plasma to CSF concentrations of free TAK‐906 was ~70:1 or 98.6% in plasma and 1.4% in CSF. At 3 hrs post dose, TAK‐906 ranged from 1.72–13.2 ng/mL. The ratio of mean plasma to mean CSF concentrations of total TAK‐906 at 3 hrs post dose on Day 4 was ~250:1. This predicts a ratio of plasma to CSF concentrations of free TAK‐906 of ~25:1 or 96% in plasma and 4% in CSF.ConclusionsSingle and repeat dose administration of TAK‐906 to rats or dogs yielded robust plasma exposures with minimal brain/CSF exposures. TAK‐906 has a preclinical profile that provides potential clinical benefits with minimal effect on brain dopaminergic receptors.Support or Funding InformationStudy was sponsored by Altos Therapeutics, LLC.