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

David J. Goldberg, Victor Zak, Bryan H. Goldstein, Shan Chen, Michelle S. Hamstra, Elizabeth A. Radojewski, Eileen Maunsell, Seema Mital, Shaji C. Menon, Kurt R. Schumacher, R. Payne, Mario Stylianou, Jonathan R. Kaltman, Tina M. deVries, James L. Yeager, Stephen M. Paridon

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)42-52
Number of pages11
JournalAmerican Heart Journal
Volume188
DOIs
StatePublished - Jun 1 2017

Fingerprint

udenafil
Cardiac Output
Vascular Resistance
Pharmacokinetics
Pharmaceutical Preparations
Exercise
Fontan Procedure
Phase III Clinical Trials
Phase II Clinical Trials
Clinical Trials, Phase I
Headache
Mouth
Cohort Studies
Pediatrics
Safety

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Goldberg, D. J., Zak, V., Goldstein, B. H., Chen, S., Hamstra, M. S., Radojewski, E. A., ... Paridon, S. M. (2017). Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation. American Heart Journal, 188, 42-52. https://doi.org/10.1016/j.ahj.2017.02.030

Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation. / Goldberg, David J.; Zak, Victor; Goldstein, Bryan H.; Chen, Shan; Hamstra, Michelle S.; Radojewski, Elizabeth A.; Maunsell, Eileen; Mital, Seema; Menon, Shaji C.; Schumacher, Kurt R.; Payne, R.; Stylianou, Mario; Kaltman, Jonathan R.; deVries, Tina M.; Yeager, James L.; Paridon, Stephen M.

In: American Heart Journal, Vol. 188, 01.06.2017, p. 42-52.

Research output: Contribution to journalArticle

Goldberg, DJ, Zak, V, Goldstein, BH, Chen, S, Hamstra, MS, Radojewski, EA, Maunsell, E, Mital, S, Menon, SC, Schumacher, KR, Payne, R, Stylianou, M, Kaltman, JR, deVries, TM, Yeager, JL & Paridon, SM 2017, 'Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation', American Heart Journal, vol. 188, pp. 42-52. https://doi.org/10.1016/j.ahj.2017.02.030
Goldberg, David J. ; Zak, Victor ; Goldstein, Bryan H. ; Chen, Shan ; Hamstra, Michelle S. ; Radojewski, Elizabeth A. ; Maunsell, Eileen ; Mital, Seema ; Menon, Shaji C. ; Schumacher, Kurt R. ; Payne, R. ; Stylianou, Mario ; Kaltman, Jonathan R. ; deVries, Tina M. ; Yeager, James L. ; Paridon, Stephen M. / Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation. In: American Heart Journal. 2017 ; Vol. 188. pp. 42-52.
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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.",
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AU - Goldberg, David J.

AU - Zak, Victor

AU - Goldstein, Bryan H.

AU - Chen, Shan

AU - Hamstra, Michelle S.

AU - Radojewski, Elizabeth A.

AU - Maunsell, Eileen

AU - Mital, Seema

AU - Menon, Shaji C.

AU - Schumacher, Kurt R.

AU - Payne, R.

AU - Stylianou, Mario

AU - Kaltman, Jonathan R.

AU - deVries, Tina M.

AU - Yeager, James L.

AU - Paridon, Stephen M.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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.

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