Pharmacokinetics of Sildenafil in Premature Infants

The purpose of this study is to learn more about the safety and dosing of sildenafil in infants.

Study Overview

• Status: Completed
• Conditions: Persistent Pulmonary Hypertension of the Newborn
• Intervention / Treatment: Drug: 1 dose of sildenafil

Detailed Description

Pharmacokinetics and safety of sildenafil will be studied in preterm infants who are receiving sildenafil per standard of care or 1 dose prescribed for the study.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249-7335
      • University of Alabama at Birmingham
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kosair Pediatric Research Unit
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • Brooklyn, New York, United States, 11203
      • Kings County Hospital Center/SUNY Downstate Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 11 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Cohort 1:

• Gestational age 28 weeks or less receiving sildenafil as standard of care < 365 postnatal days

Cohort 2:

• Gestational age 28 weeks or less
• 7-28 postnatal days of age
• Mechanical ventilation or nasal continuous positive airway pressure (NCPAP) or high-flow nasal cannula
• Intravenous line in place

Exclusion Criteria:

Cohort 1:

• Any condition that would make the participant, in the opinion of the investigator, unsuitable for the study

Cohort 2:

• Previous exposure to sildenafil within 7 days prior to enrollment
• Any condition that would make the participant, in the opinion of the investigator, unsuitable for the study
• History of allergic reactions to sildenafil
• AST > ULN or ALT > 3x ULN
• Currently on a vasopressor for hypotension
• Known sickle cell disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: sildenafil, standard of care; Infants receiving sildenafil as standard of care
Other: sildenafil administered for study; 1 dose of sildenafil administered for study	Drug: 1 dose of sildenafil; A single IV dose of sildenafil will be administered over 90 minutes with no greater than a 15-minute flush. Final dose to be determined based on at least the first 4 participants enrolled in Cohort 1; final dose expected to be a single dose between 0.25 and 0.5 mg/kg.; Other Names: Viagra; Revatio

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Area under the plasma concentration versus time curve 0-24 hours for sildenafil	IV study dose 0-15 min,1-2,3-4,12-14,24-30,48-56hr after flush.Clinical care: IV <0.5hr before dose <15 min & 3-4hr after flush <0.5hr before next dose. Enteral <0.5hr before dose, 1-2 & 3-4hr after dose, <0.5hr before next dose. 22-26hr after last dose
Peak plasma concentration of sildenafil	IV study dose 0-15 min,1-2,3-4,12-14,24-30,48-56hr after flush.Clinical care: IV <0.5hr before dose <15 min & 3-4hr after flush <0.5hr before next dose. Enteral <0.5hr before dose, 1-2 & 3-4hr after dose, <0.5hr before next dose. 22-26hr after last dose
Clearance of sildenafil	IV study dose 0-15 min,1-2,3-4,12-14,24-30,48-56hr after flush.Clinical care: IV <0.5hr before dose <15 min & 3-4hr after flush <0.5hr before next dose. Enteral <0.5hr before dose, 1-2 & 3-4hr after dose, <0.5hr before next dose. 22-26hr after last dose
Volume of distribution at steady state	IV study dose 0-15 min,1-2,3-4,12-14,24-30,48-56hr after flush.Clinical care: IV <0.5hr before dose <15 min & 3-4hr after flush <0.5hr before next dose. Enteral <0.5hr before dose, 1-2 & 3-4hr after dose, <0.5hr before next dose. 22-26hr after last dose
Half life of sildenafil	IV study dose 0-15 min,1-2,3-4,12-14,24-30,48-56hr after flush.Clinical care: IV <0.5hr before dose <15 min & 3-4hr after flush <0.5hr before next dose. Enteral <0.5hr before dose, 1-2 & 3-4hr after dose, <0.5hr before next dose. 22-26hr after last dose

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of subjects with adverse events as a measure of safety and tolerability.	From the time of the first dose to 3 days after the last dose; serious adverse events will be collected from the first dose of sildenafil to 7 days after the last dose of sildenafil
Correlation between serum and dried blood spot samples	1-7 days
Evaluate P450 single nucleotide polymorphisms (SNPs)	2-7 days

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Duke University; The Emmes Company, LLC
• Investigators: Principal Investigator: Matthew M Laughon, MD, MPH, University of North Carolina

Publications and helpful links

General Publications

• Jackson W, Gonzalez D, Smith PB, Ambalavanan N, Atz AM, Sokol GM, Hornik CD, Stewart D, Mundakel G, Poindexter BB, Ahlfeld SK, Mills M, Cohen-Wolkowiez M, Martz K, Hornik CP, Laughon MM; Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee. Safety of sildenafil in extremely premature infants: a phase I trial. J Perinatol. 2022 Jan;42(1):31-36. doi: 10.1038/s41372-021-01261-w. Epub 2021 Nov 5.

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: August 17, 2012
• First Submitted That Met QC Criteria: August 20, 2012
• First Posted (Estimate): August 21, 2012

Study Record Updates

• Last Update Posted (Estimate): November 2, 2016
• Last Update Submitted That Met QC Criteria: November 1, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: persistent pulmonary hypertension of the newborn; sildenafil; preterm infants
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Hypertension; Hypertension, Pulmonary; Persistent Fetal Circulation Syndrome; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: 11-1646; HHSN27500014 (Other Grant/Funding Number: NICHD)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO