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.