Abstract
To investigate the impact of the direct Factor Xa inhibitor darexaban administered in a modified-release formulation (darexaban-MR) on the pharmacokinetic (PK) profile of digoxin. In this Phase I, randomized, double-blind, two-period crossover study (8 days for each treatment, 10 days washout), 24 healthy subjects received darexaban-MR 120 mg once/day (qd) + digoxin 0.25 mg qd in one treatment period, and placebo + digoxin 0.25 mg qd in the other treatment period. Blood for PK assessment of digoxin and darexaban was obtained in serial profile on day 8, as well as pre-dose on day 6–7; urinary PK samples were obtained up to 24 h after the last dose on day 8. A lack of interaction was determined if 90 % confidence intervals (CIs) for the geometric mean ratios (GMR) of digoxin C max,ss and AUC0–24h,ss with and without darexaban-MR co-administration were within 0.80–1.25 limits. Pharmacodynamic activity was assessed by international normalized ratio and activated partial thromboplastin time. Twenty-three subjects completed the study. The GMR (90 % CI) for C max,ss and AUC0–24h,ss of digoxin plus darexaban versus digoxin plus placebo was 1.03 (90 % CI: 0.94–1.12) and 1.11 (90 % CI: 1.05–1.17), respectively. The 90 % CI for the GMRs fell within the limits of 0.80–1.25, indicating a lack of drug–drug interaction. Co-administration of digoxin with darexaban-MR was well tolerated, with no unexpected treatment-emergent adverse events or safety concerns. Co-administration of darexaban-MR did not impact the steady-state PK profile of digoxin.
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Acknowledgments
This study was funded by Astellas. Editorial support was provided by Medicus International and funded by Astellas. Takeshi Kadokura is an employee of Astellas Pharma Inc. Dorien Groenendaal, Alberto Garcia-Hernandez, Marten Heeringa, Roelof Mol, Frank Verheggen, and Hartmut Onkels are all employees of Astellas Pharma Global Development Europe.
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ClinicalTrials.gov identifier: NCT01514812.
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Kadokura, T., Groenendaal, D., Heeringa, M. et al. Darexaban (YM150), an oral direct factor Xa inhibitor, has no effect on the pharmacokinetics of digoxin. Eur J Drug Metab Pharmacokinet 39, 1–9 (2014). https://doi.org/10.1007/s13318-013-0141-1
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DOI: https://doi.org/10.1007/s13318-013-0141-1