Association between oral sildenafil dosing, predicted exposure, and systemic hypotension in hospitalised infants

Hornik, Christoph P.; Onufrak, Nikolas J.; Smith, P. Brian; Cohen‐Wolkowiez, Michael; Laughon, Matthew M.; Clark, Reese H.; González, Daniel

doi:10.1017/s1047951117001639

Cited by 5 publications

(3 citation statements)

References 30 publications

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“…While the PK results from this study determined that co-administration of fluconazole reduced sildenafil clearance [13], our ability to relate reduced drug clearance with safety is limited by the small number of participants receiving fluconazole (n = 4). However, a retrospective analysis of electronic health records data from this group did not identify a clear relationship between simulated sildenafil exposure and hypotension [28]. Despite these limitations, this study provides an important first step in evaluating sildenafil as a potential therapy for premature infants with or developing BPD and PH.…”

Section: Discussionmentioning

confidence: 82%

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

et al. 2021

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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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Section: Discussionmentioning

confidence: 82%

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

et al. 2021

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“…18,[48][49][50][51] The PTN has also leveraged EHR data as an innovative tool in pharmacometric analyses, a critically important step in pediatric drug development in concert with the Food and Drug Administration. 17,[52][53][54][55][56] Despite these successes, more widespread application of EHR data within the PTN is contingent upon access to detailed clinical information including drug administration, laboratory results, vital signs, diagnoses and procedures, and clinical assessments. Data sources from previous PTN collaborating networks including the Pediatrix Medical Group Clinical Data Warehouse do not routinely capture this level of detail, collaborations with CER 2 were focused on outpatient data, and site-based collection of data from the EHR for a specific study is resource-consuming and inefficient.…”

Section: Discussionmentioning

confidence: 99%

Creation of a Multicenter Pediatric Inpatient Data Repository Derived from Electronic Health Records

et al. 2019

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Background Integration of electronic health records (EHRs) data across sites and access to that data remain limited. Objective We developed an EHR-based pediatric inpatient repository using nine U.S. centers from the National Institute of Child Health and Human Development Pediatric Trials Network. Methods A data model encompassing 147 mandatory and 99 optional elements was developed to provide an EHR data extract of all inpatient encounters from patients <17 years of age discharged between January 6, 2013 and June 30, 2017. Sites received instructions on extractions, transformation, testing, and transmission to the coordinating center. Results We generated 177 staging reports to process all nine sites' 147 mandatory and 99 optional data elements to the repository. Based on 520 prespecified criteria, all sites achieved 0% errors and <2% warnings. The repository includes 386,159 inpatient encounters from 264,709 children to support study design and conduct of future trials in children. Conclusion Our EHR-based data repository of pediatric inpatient encounters utilized a customized data model heavily influenced by the PCORnet format, site-based data mapping, a comprehensive set of data testing rules, and an iterative process of data submission. The common data model, site-based extraction, and technical expertise were key to our success. Data from this repository will be used in support of Pediatric Trials Network studies and the labeling of drugs and devices for children.

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“…Neonates with PH generally have a distinct right-to-left shunting across the foramen ovale or ductus arteriosus, and sildenafil infusion may promote hypotension via direct delivery to the systemic vascular system (46). Recently, a large, novel sildenafil exposure-safety study involving 232 hospitalized neonates reported that neither dosing nor exposure was associated with systemic hypotension in a multivariable analysis (63). However, hypotension is more common with intravenous than with oral sildenafil, and it may be of clinical significance to evaluate this adverse effect in a retrospective study of intravenous sildenafil.…”

Section: Adverse Effects Of Sildenafil Use In Neonatesmentioning

confidence: 99%

Update on the use of sildenafil in neonatal pulmonary hypertension: a narrative review of the history, current administration, and future directions

Li¹,

Lv²,

Liu³

et al. 2021

Transl Pediatr

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Pulmonary hypertension (PH) is a life-threatening syndrome in neonates and has multiple and varied etiologies. However, few clinical studies have systematically evaluated the treatment regimens for this population. Phosphodiesterase (PDE) inhibitors, such as milrinone, tadalafil, dipyridamole, and sildenafil, are the most important regulators of vascular relaxation in the normal pulmonary vascular transition after birth, and these agents are widely used in the treatment of PH. Sildenafil, a representative PDE-5 inhibitor, has an important role as a single mode of therapy. However, the lack of evidence from pharmacokinetic and clinical trials has limited the emergence of standardized treatment regimens for sildenafil. There are also differing opinions among researchers regarding the best route of sildenafil administration. Due to the interindividual variability in the neonatal population, it is worth selecting the most suitable route of sildenafil administration according to the specific conditions of the neonatal population. These may be evaluated using the oxygenation index (OI), pulmonary artery pressure, mean blood pressure, and the serological index. This article reviews the clinical data on the use of sildenafil, focusing on the current and promising alternative routes of administration, which may affect subsequent clinical research in term and preterm neonates.

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Association between oral sildenafil dosing, predicted exposure, and systemic hypotension in hospitalised infants

Cited by 5 publications

References 30 publications

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

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

Creation of a Multicenter Pediatric Inpatient Data Repository Derived from Electronic Health Records

Update on the use of sildenafil in neonatal pulmonary hypertension: a narrative review of the history, current administration, and future directions

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