Safety of sildenafil in extremely premature infants: a phase I trial

doi:10.1038/s41372-021-01261-w

Clinical Trial

. 2022 Jan;42(1):31-36.

doi: 10.1038/s41372-021-01261-w. Epub 2021 Nov 5.

Safety of sildenafil in extremely premature infants: a phase I trial

Wesley Jackson¹, Daniel Gonzalez², P Brian Smith^{3

4}, Namasivayam Ambalavanan⁵, Andrew M Atz⁶, Gregory M Sokol⁷, Chi D Hornik^{3

4}, Dan Stewart⁸, Gratias Mundakel⁹, Brenda B Poindexter¹⁰, Shawn K Ahlfeld¹¹, Mary Mills⁴, Michael Cohen-Wolkowiez^{3

4}, Karen Martz¹², Christoph P Hornik^{3

4}, Matthew M Laughon¹³; Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee

Affiliations

¹ Department of Pediatrics, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. wesley.jackson@unc.edu.
² Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
⁴ Duke Clinical Research Institute, Durham, NC, USA.
⁵ Division of Neonatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
⁶ Department of Pediatrics, Medical University of South Carolina Children's Hospital, Charleston, SC, USA.
⁷ Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
⁸ University of Louisville Norton Children's Hospital, Louisville, KY, USA.
⁹ Kings County Hospital Center/SUNY Downstate Medical Center, Brooklyn, NY, USA.
¹⁰ Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, GA, USA.
¹¹ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹² The Emmes Company, LLC, Rockville, MD, USA.
¹³ Department of Pediatrics, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

PMID: 34741102
PMCID: PMC8569839
DOI: 10.1038/s41372-021-01261-w

Clinical Trial

Safety of sildenafil in extremely premature infants: a phase I trial

Wesley Jackson et al. J Perinatol. 2022 Jan.

. 2022 Jan;42(1):31-36.

doi: 10.1038/s41372-021-01261-w. Epub 2021 Nov 5.

Authors

Affiliations

¹ Department of Pediatrics, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. wesley.jackson@unc.edu.
² Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
⁴ Duke Clinical Research Institute, Durham, NC, USA.
⁵ Division of Neonatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
⁶ Department of Pediatrics, Medical University of South Carolina Children's Hospital, Charleston, SC, USA.
⁷ Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
⁸ University of Louisville Norton Children's Hospital, Louisville, KY, USA.
⁹ Kings County Hospital Center/SUNY Downstate Medical Center, Brooklyn, NY, USA.
¹⁰ Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, GA, USA.
¹¹ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹² The Emmes Company, LLC, Rockville, MD, USA.
¹³ Department of Pediatrics, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

PMID: 34741102
PMCID: PMC8569839
DOI: 10.1038/s41372-021-01261-w

Abstract

Objective: To characterize the safety of sildenafil in premature infants.

Study design: A phase I, open-label trial of sildenafil in premature infants receiving sildenafil per usual clinical care (cohort 1) or receiving a single IV dose of sildenafil (cohort 2). Safety was evaluated based on adverse events (AEs), transaminase levels, and mean arterial pressure monitoring.

Results: Twenty-four infants in cohort 1 (n = 25) received enteral sildenafil. In cohort 2, infants received a single IV sildenafil dose of 0.25 mg/kg (n = 7) or 0.125 mg/kg (n = 2). In cohort 2, there was one serious AE related to study drug involving hypotension associated with a faster infusion rate than specified by the protocol. There were no AEs related to elevated transaminases.

Conclusion: Sildenafil was well tolerated by the study population. Drug administration times and flush rates require careful attention to prevent infusion-related hypotension associated with faster infusions of IV sildenafil in premature infants.

Clinical trial: ClinicalTrials.gov Identifier: NCT01670136.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Change from baseline Mean Arterial Pressure (MAP) over time following start of IV sildenafil infusion.**
a The dose group 0.25 mg/kg and b dose group 0.125 mg/kg in a phase I study of sildenafil in premature infants. Circles represent median change and whiskers represent minimum and maximum value.

See this image and copyright information in PMC

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References

1. Mourani PM, Sontag MK, Younoszai A, Miller JI, Kinsella JP, Baker CD, et al. Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2015;191:87–95. doi: 10.1164/rccm.201409-1594OC. - DOI - PMC - PubMed
1. Collaco JM, Dadlani GH, Nies MK, Leshko J, Everett AD, McGrath-Morrow SA. Risk factors and clinical outcomes in preterm infants with pulmonary hypertension. PLoS One. 2016;11:e0163904. doi: 10.1371/journal.pone.0163904. - DOI - PMC - PubMed
1. An HS, Bae EJ, Kim GB, Kwon BS, Beak JS, Kim EK, et al. Pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. Korean Circ J. 2010;40:131–6. doi: 10.4070/kcj.2010.40.3.131. - DOI - PMC - PubMed
1. Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics. 2007;120:1260–9. doi: 10.1542/peds.2007-0971. - DOI - PubMed
1. Slaughter JL, Pakrashi T, Jones DE, South AP, Shah TA. Echocardiographic detection of pulmonary hypertension in extremely low birth weight infants with bronchopulmonary dysplasia requiring prolonged positive pressure ventilation. J Perinatol. 2011;31:635–40. doi: 10.1038/jp.2010.213. - DOI - PubMed

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[1] Mourani PM, Sontag MK, Younoszai A, Miller JI, Kinsella JP, Baker CD, et al. Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2015;191:87–95. doi: 10.1164/rccm.201409-1594OC. - DOI - PMC - PubMed

[2] Mourani PM, Sontag MK, Younoszai A, Miller JI, Kinsella JP, Baker CD, et al. Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2015;191:87–95. doi: 10.1164/rccm.201409-1594OC. - DOI - PMC - PubMed

[3] Collaco JM, Dadlani GH, Nies MK, Leshko J, Everett AD, McGrath-Morrow SA. Risk factors and clinical outcomes in preterm infants with pulmonary hypertension. PLoS One. 2016;11:e0163904. doi: 10.1371/journal.pone.0163904. - DOI - PMC - PubMed

[4] Collaco JM, Dadlani GH, Nies MK, Leshko J, Everett AD, McGrath-Morrow SA. Risk factors and clinical outcomes in preterm infants with pulmonary hypertension. PLoS One. 2016;11:e0163904. doi: 10.1371/journal.pone.0163904. - DOI - PMC - PubMed

[5] An HS, Bae EJ, Kim GB, Kwon BS, Beak JS, Kim EK, et al. Pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. Korean Circ J. 2010;40:131–6. doi: 10.4070/kcj.2010.40.3.131. - DOI - PMC - PubMed

[6] An HS, Bae EJ, Kim GB, Kwon BS, Beak JS, Kim EK, et al. Pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. Korean Circ J. 2010;40:131–6. doi: 10.4070/kcj.2010.40.3.131. - DOI - PMC - PubMed

[7] Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics. 2007;120:1260–9. doi: 10.1542/peds.2007-0971. - DOI - PubMed

[8] Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics. 2007;120:1260–9. doi: 10.1542/peds.2007-0971. - DOI - PubMed

[9] Slaughter JL, Pakrashi T, Jones DE, South AP, Shah TA. Echocardiographic detection of pulmonary hypertension in extremely low birth weight infants with bronchopulmonary dysplasia requiring prolonged positive pressure ventilation. J Perinatol. 2011;31:635–40. doi: 10.1038/jp.2010.213. - DOI - PubMed

[10] Slaughter JL, Pakrashi T, Jones DE, South AP, Shah TA. Echocardiographic detection of pulmonary hypertension in extremely low birth weight infants with bronchopulmonary dysplasia requiring prolonged positive pressure ventilation. J Perinatol. 2011;31:635–40. doi: 10.1038/jp.2010.213. - DOI - PubMed

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Safety of sildenafil in extremely premature infants: a phase I trial

Affiliations

Safety of sildenafil in extremely premature infants: a phase I trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

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Cited by

References

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Associated data

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LinkOut - more resources

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Medical

Abstract

Conflict of interest statement

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Medical