Evaluation of the Pharmacokinetics of Trazpiroben (TAK-906), a Peripherally Selective D2/D3 Dopamine Receptor Antagonist, in the Presence and Absence of Itraconazole, a Potent CYP 3A4 Inhibitor.

Abstract

Purpose: Treatment options for gastroparesis, such as metoclopramide and domperidone, are limited because of safety concerns, which may be exacerbated in the presence of inhibitors of drug metabolism. This study evaluated the effect of itraconazole on the pharmacokinetics, safety, and tolerability of trazpiroben (previously TAK-906), a novel, peripherally selective D₂/D₃ dopamine receptor antagonist.

Methods: This was a phase 1, two-period, crossover trial in healthy participants (NCT03161405). On day 1, period 1 (days 1-3), participants received a single oral dose of trazpiroben 25 mg. During period 2 (days 4-9), participants received oral itraconazole 200 mg once daily (days 1-5) and one oral dose of trazpiroben 25 mg post itraconazole on day 4. Trazpiroben pharmacokinetics were assessed. Safety assessments included triplicate electrocardiograms.

Results: Twelve healthy males (24-45 years old) were studied. Co-administration of itraconazole increased trazpiroben area under the concentration-time curve from time 0 to infinity by 1.28-fold (90% confidence interval: 1.10, 1.49) and maximum plasma concentration (C_max) by 1.98-fold (1.64, 2.39) versus trazpiroben alone. Placebo-corrected, change from baseline in corrected QT interval at the observed geometric mean C_max for trazpiroben alone (9.53 ng/mL) and with itraconazole (18.00 ng/mL) was estimated at 1.31 ms (-0.39, 3.01) and 1.54 ms (-0.15, 3.24), respectively. There were no clinically relevant abnormalities in any safety parameters.

Conclusion: These results indicate that TAK‑906 is relatively insensitive to inhibition of cytochrome P450 3A4, and cardiovascular safety concerns associated with domperidone are unlikely to be elicited by trazpiroben under similar conditions.