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Am Heart J. 2017 Jun;188:42-52. doi: 10.1016/j.ahj.2017.02.030. Epub 2017 Mar 6.

Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation.

Author information

1
Division of Cardiology, The Children's Hospital of Philadelphia, Perelman School of Medicine, Philadelphia, PA. Electronic address: goldbergda@email.chop.edu.
2
New England Research Institutes, Watertown, MA.
3
Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
4
Division of Cardiology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario.
5
Division of Cardiology, Primary Children's Hospital, Salt Lake City, UT.
6
Division of Cardiology, C.S. Mott Children's Hospital, Ann Arbor, MI.
7
Division of Cardiology, Riley Hospital for Children, Indianapolis, IN.
8
Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD.
9
Consultant to Mezzion Pharma Co. Ltd., Mezzion Pharma Co. Ltd., Seoul, South Korea.
10
Division of Cardiology, The Children's Hospital of Philadelphia, Perelman School of Medicine, Philadelphia, PA.

Abstract

BACKGROUND:

The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes.

OBJECTIVES:

This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan.

METHODS:

A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five.

RESULTS:

The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts.

CONCLUSIONS:

Udenafil was well-tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial.

PMID:
28577680
PMCID:
PMC5458626
DOI:
10.1016/j.ahj.2017.02.030
[Indexed for MEDLINE]
Free PMC Article

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