Aims: The C-X-C chemokine receptor 3 (CXCR3) axis is highly upregulated in the tissue of patients with type 1 diabetes. Antagonizing CXCR3 may reduce the migration of CXCR3-expressing cells to the pancreas. The pharmacokinetics (PKs), target engagement (TE) (inhibition of CXCR3 internalization) and safety of single- and multiple-ascending doses (SADs and MADs) of ACT-777991, a novel orally available potent CXCR3 antagonist, were assessed in a double-blind, randomized, placebo-controlled phase 1 study.
Methods: Doses up to 100 mg (SAD part) and 40 mg twice daily (MAD part) were investigated in a total of 70 male and female healthy participants. Food effect was integrated as an SAD subpart. PK, TE, safety and tolerability data were collected up to 4 days after (last) dosing.
Results: In both SAD and MAD parts, ACT-777991 was rapidly absorbed with a time to reach maximum concentration between 0.5 and 1.5 h post dose, followed by a biphasic disposition with a terminal half-life between 9.7 and 10.3 h. Increase in exposure and maximum concentration of ACT-777991 were dose-proportional. Steady state was reached after 48 h with minimal accumulation. The rate but not the extent of absorption was modified by food intake. A dose-dependent TE was demonstrated in both SAD and MAD parts. ACT-777991 was well tolerated. Neither a treatment-related pattern nor a dose-response relationship was determined for adverse events or any safety variable. No QT prolongation liability of regulatory concern was detected.
Conclusions: In this first-in-human study, ACT-777991 showed good tolerability for all doses tested and a PK and TE profile suitable for further clinical development.
Keywords: C-X-C chemokine receptor 3; first-in-human; pharmacodynamics; pharmacokinetics; safety and tolerability.
© 2023 British Pharmacological Society.