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

Abstract

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.

Multi-dose enteral L-citrulline administration in premature infants at risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia

“…Future Phase II studies need to be conducted in a larger number of patients to more completely evaluate the dosing strategies needed to achieve targeted steady-state plasma concentrations. Consistent with the experience of other investigators [ 37 ], we believe that one obstacle to successfully enrolling fragile patients into phase I studies like ours is that their parents were reluctant to grant consent for a study that had no direct benefit. Another issue is that none of our patients required invasive respiratory support at the time of study.…”

Multi-dose enteral L-citrulline administration in premature infants at risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia

“…Future Phase II studies need to be conducted in a larger number of patients to more completely evaluate the dosing strategies needed to achieve targeted steady-state plasma concentrations. Consistent with the experience of other investigators 35 , we believe that one obstacle to successfully enrolling fragile patients into phase I studies like ours is that their parents were reluctant to grant consent for a study that had no direct bene t. Another limitation is that because we performed the study with premature infants, we used a limited sampling strategy and collected only two blood samples per patient. We were also limited by not knowing the actual steady-state L-citrulline concentrations that will achieve therapeutic e cacy.…”

Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial

“…The initial dose of 0.125 mg/kg IV (or 0.25 mg enteral) every 8 h was chosen based on our phase I study (NCT01670136). In the phase I study, we enrolled 25 premature infants born at or before 28 weeks gestation who received standard of care doses of 0.5–2.25 mg/kg enteral sildenafil at 7–40 days of life [ 32 , 33 ]. A second cohort of 9 similar infants received a single 0.25 mg/kg IV dose.…”

“…The trial enrolled 9 additional infants ≤28 weeks' gestational age and postnatal age range 7–40 days who received a single intravenous dose of sildenafil 0.25 mg/kg or 0.125 mg/kg in a second cohort. These data indicated a one compartment model and that the enteral to IV conversion of 2:1 would be appropriate, and provided dosing levels for the current sequential cohort study [ 32 , 33 ].…”