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

Chunlin Chen,1 Wenwen Zhang,1 Muhammad Bari,2 Cristina Almansa,1 Mike Baratta,1 Maria Rosario1 1Takeda Development Center Americas, Inc, Cambridge, MA, USA; 2Takeda International UK, Ltd, High Wycombe, UKCorrespondence: Chunlin Chen Email chen_chunlin@hotmail.comPurpose: Treatment options for gastro...

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Autores principales:	Chen C, Zhang W, Bari M, Almansa C, Baratta M, Rosario M
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	drug–drug interactions d2/d3 dopamine receptor antagonist gastroparesis pharmacokinetics qt effects Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/21f99724e4c04856a4b856681fd30696
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spelling	oai:doaj.org-article:21f99724e4c04856a4b856681fd306962021-12-02T16:11:44ZEvaluation 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 Inhibitor1179-1438https://doaj.org/article/21f99724e4c04856a4b856681fd306962021-07-01T00:00:00Zhttps://www.dovepress.com/evaluation-of-the-pharmacokinetics-of-trazpiroben-tak-906-a-peripheral-peer-reviewed-fulltext-article-CPAAhttps://doaj.org/toc/1179-1438Chunlin Chen,1 Wenwen Zhang,1 Muhammad Bari,2 Cristina Almansa,1 Mike Baratta,1 Maria Rosario1 1Takeda Development Center Americas, Inc, Cambridge, MA, USA; 2Takeda International UK, Ltd, High Wycombe, UKCorrespondence: Chunlin Chen Email chen_chunlin@hotmail.comPurpose: 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 (Cmax) 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 Cmax 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.Keywords: drug–drug interactions, D2/D3 dopamine receptor antagonist, gastroparesis, pharmacokinetics, QT effectsChen CZhang WBari MAlmansa CBaratta MRosario MDove Medical Pressarticledrug–drug interactionsd2/d3 dopamine receptor antagonistgastroparesispharmacokineticsqt effectsTherapeutics. PharmacologyRM1-950ENClinical Pharmacology: Advances and Applications, Vol Volume 13, Pp 145-155 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	drug–drug interactions d2/d3 dopamine receptor antagonist gastroparesis pharmacokinetics qt effects Therapeutics. Pharmacology RM1-950
spellingShingle	drug–drug interactions d2/d3 dopamine receptor antagonist gastroparesis pharmacokinetics qt effects Therapeutics. Pharmacology RM1-950 Chen C Zhang W Bari M Almansa C Baratta M Rosario M 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
description	Chunlin Chen,1 Wenwen Zhang,1 Muhammad Bari,2 Cristina Almansa,1 Mike Baratta,1 Maria Rosario1 1Takeda Development Center Americas, Inc, Cambridge, MA, USA; 2Takeda International UK, Ltd, High Wycombe, UKCorrespondence: Chunlin Chen Email chen_chunlin@hotmail.comPurpose: 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 (Cmax) 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 Cmax 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.Keywords: drug–drug interactions, D2/D3 dopamine receptor antagonist, gastroparesis, pharmacokinetics, QT effects
format	article
author	Chen C Zhang W Bari M Almansa C Baratta M Rosario M
author_facet	Chen C Zhang W Bari M Almansa C Baratta M Rosario M
author_sort	Chen C
title	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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/21f99724e4c04856a4b856681fd30696
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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

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