https://orcid.org/0000-0003-2241-8865
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 (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.
Acknowledgments
Medical writing assistance was provided by Fraser Harris and Alex Kisbey of Oxford PharmaGenesis Ltd, Oxford, UK, and was supported by Takeda Pharmaceutical Company, Ltd.
Abbreviations
ADR, adverse drug reaction; AE, adverse event; AUC0–∞, area under the concentration–time curve from time 0 to infinity; AUC0–last, area under the concentration–time curve from time 0 to the last quantifiable concentration; BMI, body mass index; CI, confidence interval; Cmax, maximum plasma concentration; CYP, cytochrome P450; ECG, electrocardiogram; EMA, European Medicines Agency; FDA, Food and Drug Administration; P-GP, P-glycoprotein; QTcF, QT interval corrected for heart rate by the Fridericia method; t1/2z, terminal disposition phase half-life; tmax, time to maximum plasma concentration.
Data Sharing Statement
Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda’s Data Sharing Policy (see https://www.takedaclinicaltrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor’s qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment. The datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participant data supporting the results reported in this manuscript, will be available three months from initial request, to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification, in compliance with applicable privacy laws, data protection and requirements for consent and anonymization.
Ethics Approval
All procedures performed in this trial were approved and conducted in compliance with the institutional review board regulations of the US Code of Federal Regulations, Good Clinical Practice regulations and guidelines, and all applicable local regulations, and in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Consent to Participate
This trial was conducted in compliance with the informed consent regulations and all patients provided signed informed consent forms prior to enrolment in the trial standards.
Author Contributions
C Chen, W Zhang, M Bari, C Almansa, M Baratta, and M Rosario designed the trial, analyzed the data, wrote, and reviewed the manuscript. All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.
Disclosure
C Chen was an employee of Takeda Development Center Americas, Inc. at the time the study was performed and received stock or stock options; he is currently an employee of Bayer Pharmaceuticals, Whippany, NJ, USA. W Zhang and M Baratta are employees of Takeda Development Center Americas, Inc. and receive stock or stock options. M Bari was an employee of Takeda International UK, Ltd. at the time the study was performed and received stock or stock options; he is currently Medical Director at New Medicines Ltd., Manchester, UK. C Almansa was an employee of Takeda Pharmaceuticals and received stock or stock options at the time of the study, and is currently an employee of Ironwood Pharmaceuticals, Boston, MA, USA. M Rosario was an employee of Takeda Pharmaceuticals and received stock or stock options at the time of the study, and is currently an employee of Syros Pharmaceuticals Inc., Cambridge, MA, USA. The authors report no other conflicts of interest in this work.