Skip to main content Accessibility help
×
Home
Hostname: page-component-cf9d5c678-xvx2z Total loading time: 0.348 Render date: 2021-08-05T17:53:55.187Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "metricsAbstractViews": false, "figures": true, "newCiteModal": false, "newCitedByModal": true, "newEcommerce": true, "newUsageEvents": true }

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

Published online by Cambridge University Press:  08 August 2017

Christoph P. Hornik
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Duke University, Durham, North Carolina, United States of America
Nikolas J. Onufrak
Affiliation:
Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
P. Brian Smith
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Duke University, Durham, North Carolina, United States of America
Michael Cohen-Wolkowiez
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Duke University, Durham, North Carolina, United States of America
Matthew M. Laughon
Affiliation:
Department of Pediatrics, Division of Neonatology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
Reese H. Clark
Affiliation:
Pediatrix-Obstetrix Center for Research and Education, Sunrise, Florida, United States of America
Daniel Gonzalez
Affiliation:
Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
Corresponding
E-mail address:

Abstract

Background

The relationship between sildenafil dosing, exposure, and systemic hypotension in infants is incompletely understood.

Objectives

The aim of this study was to characterise the relationship between predicted sildenafil exposure and hypotension in hospitalised infants.

Methods

We extracted information on sildenafil dosing and clinical characteristics from electronic health records of 348 neonatal ICUs from 1997 to 2013, and we predicted drug exposure using a population pharmacokinetic model.

Results

We identified 232 infants receiving sildenafil at a median dose of 3.2 mg/kg/day (2.0, 6.0). The median steady-state area under the concentration–time curve over 24 hours (AUC24,SS) and maximum concentration of sildenafil (Cmax,SS,SIL) were 712 ng×hour/ml (401, 1561) and 129 ng/ml (69, 293), respectively. Systemic hypotension occurred in 9% of the cohort. In multivariable analysis, neither dosing nor exposure were associated with systemic hypotension: odds ratio=0.96 (95% confidence interval: 0.81, 1.14) for sildenafil dose; 0.87 (0.59, 1.28) for AUC24,SS; 1.19 (0.78, 1.82) for Cmax,SS,SIL.

Conclusions

We found no association between sildenafil dosing or exposure with systemic hypotension. Continued assessment of sildenafil’s safety profile in infants is warranted.

Type
Original Articles
Copyright
© Cambridge University Press 2017 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Steinhorn, RH. Pharmacotherapy for pulmonary hypertension. Pediatr Clin North Am 2012; 59: 11291146.CrossRefGoogle ScholarPubMed
2. Porta, NF, Steinhorn, RH. Pulmonary vasodilator therapy in the NICU: inhaled nitric oxide, sildenafil, and other pulmonary vasodilating agents. Clin Perinatol 2012; 39: 149164.CrossRefGoogle ScholarPubMed
3. Buxton, N, Flannery, T, Wild, D, Bassi, S. Sildenafil (Viagra)-induced spontaneous intracerebral haemorrhage. Br J Neurosurg 2001; 15: 347349.CrossRefGoogle ScholarPubMed
4. Samada, K, Shiraishi, H, Aoyagi, J, Momoi, MY. Cerebral hemorrhage associated with sildenafil (Revatio) in an infant. Pediatr Cardiol 2009; 30: 998999.CrossRefGoogle Scholar
5. Baquero, H, Soliz, A, Neira, F, Venegas, ME, Sola, A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatr 2006; 117: 10771083.CrossRefGoogle ScholarPubMed
6. Steinhorn, RH. Diagnosis and treatment of pulmonary hypertension in infancy. Early Hum Dev 2013; 89: 865874.CrossRefGoogle ScholarPubMed
7. Steinhorn, RH, Kinsella, JP, Pierce, C, et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr 2009; 155: 841847 e1.CrossRefGoogle ScholarPubMed
8. Mourani, PM, Sontag, MK, Ivy, DD, Abman, SH. Effects of long-term sildenafil treatment for pulmonary hypertension in infants with chronic lung disease. J Pediatr 2009; 154: 379384. e1-2.CrossRefGoogle ScholarPubMed
9. Limjoco, J, Paquette, L, Ramanathan, R, Seri, I, Friedlich, P. Changes in mean arterial blood pressure during sildenafil use in neonates with meconium aspiration syndrome or sepsis. Am J Ther 2015; 22: 125131.CrossRefGoogle ScholarPubMed
10. Vassalos, A, Peng, E, Young, D, et al. Pre-operative sildenafil and pulmonary endothelial-related complications following cardiopulmonary bypass: a randomised trial in children undergoing cardiac surgery. Anaesthes 2011; 66: 472480.CrossRefGoogle ScholarPubMed
11. Ahsman, MJ, Witjes, BC, Wildschut, ED, et al. Sildenafil exposure in neonates with pulmonary hypertension after administration via a nasogastric tube. Arch Dis Child Fetal Neonatal Ed 2010; 95: F109F114.CrossRefGoogle Scholar
12. Mukherjee, A, Dombi, T, Wittke, B, Lalonde, R. Population pharmacokinetics of sildenafil in term neonates: evidence of rapid maturation of metabolic clearance in the early postnatal period. Clin Pharmacol Ther 2009; 85: 5663.CrossRefGoogle ScholarPubMed
13. Laughon, MM, Benjamin, DK Jr, Capparelli, EV, et al. Innovative clinical trial design for pediatric therapeutics. Expert Rev Clin Pharmacol 2011; 4: 643652.CrossRefGoogle ScholarPubMed
14. Laughon, MM, Benjamin, DK Jr. Mechanisms to provide safe and effective drugs for children. Pediatr 2014; 134: e562e563.CrossRefGoogle ScholarPubMed
15. Spitzer, AR, Ellsbury, DL, Handler, D, Clark, RH. The Pediatrix BabySteps Data Warehouse and the Pediatrix QualitySteps improvement project system – tools for “meaningful use” in continuous quality improvement. Clin Perinatol 2010; 37: 4970.CrossRefGoogle Scholar
16. Olsen, IE, Groveman, SA, Lawson, ML, Clark, RH, Zemel, BS. New intrauterine growth curves based on United States data. Pediatr 2010; 125: e214e224.CrossRefGoogle ScholarPubMed
17. Samiee-Zafarghandy, S, Smith, PB, van den Anker, JN. Safety of sildenafil in infants. Pediatr Crit Care Med 2014; 15: 362368.CrossRefGoogle ScholarPubMed
18. McLaughlin, VV, McGoon, MD. Pulmonary arterial hypertension. Circulation 2006; 114: 14171431.CrossRefGoogle ScholarPubMed
19. Galie, N, Ghofrani, HA, Torbicki, A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353: 21482157.CrossRefGoogle ScholarPubMed
20. Shekerdemian, LS, Ravn, HB, Penny, DJ. Interaction between inhaled nitric oxide and intravenous sildenafil in a porcine model of meconium aspiration syndrome. Pediatr Res 2004; 55: 413418.CrossRefGoogle Scholar
21. Farrow, KN, Groh, BS, Schumacker, PT, et al. Hyperoxia increases phosphodiesterase 5 expression and activity in ovine fetal pulmonary artery smooth muscle cells. Circ Res 2008; 102: 226233.CrossRefGoogle ScholarPubMed
22. Vargas-Origel, A, Gomez-Rodriguez, G, Aldana-Valenzuela, C, et al. The use of sildenafil in persistent pulmonary hypertension of the newborn. Am J Perinatol 2010; 27: 225230.CrossRefGoogle Scholar
23. Kearns, GL. Selecting the proper pediatric dose: it is more than size that matters. Clin Pharmacol Ther 2015; 98: 238240.CrossRefGoogle ScholarPubMed
24. Holford, N. Dosing in children. Clin Pharmacol Ther 2010; 87: 367370.CrossRefGoogle ScholarPubMed
25. Thakkar, N, Gonzalez, D, Cohen-Wolkowiez, M, et al. An opportunistic study evaluating pharmacokinetics of sildenafil for the treatment of pulmonary hypertension in infants. J Perinatol 2016; 36: 744747.CrossRefGoogle ScholarPubMed
26. Barst, RJ, Beghetti, M, Pulido, T, et al. STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension. Circulation 2014; 129: 19141923.CrossRefGoogle ScholarPubMed
27. Barst, RJ, Ivy, DD, Gaitan, G, et al. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation, 125: 324334.CrossRefGoogle ScholarPubMed
28. US Food and Drug Administration. Revatio (sildenafil): Drug Safety Communication-Recommendation against use in children. Retrieved April 20, 2016, from http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucsm317743.htm.Google Scholar
29. US Food and Drug Administration. Medical, statistical, and clinical pharmacology reviews of pediatric studies conducted under Section 505A and 505B of the Federal Food, Drug, and Cosmetic Act, as amended by the FDA Amendments Act of 2012 (FDASIA). Retrieved May 3, 2016, from http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM320473.pdf.Google Scholar
30. Dodgen, AL, Hill, KD. Safety and tolerability considerations in the use of sildenafil for children with pulmonary arterial hypertension. Drug Healthc Patient Saf 2015; 7: 175183.Google Scholar
31. Kraemer, U, Wildschuth, E, Tibboel, D. “Out of the blue”-safety and efficacy of pulmonary hypertension treatment in childhood. Pediatr Crit Care Med 2014; 15: 377378.CrossRefGoogle ScholarPubMed
32. England, A, Wade, K, Smith, PB, Berezny, K, Laughon, M. Optimizing operational efficiencies in early phase trials: the Pediatric Trials Network experience. Contemp Clin Trials 2016; 47: 376382.CrossRefGoogle ScholarPubMed
Supplementary material: File

Hornik supplementary material

Table S1

Download Hornik supplementary material(File)
File 13 KB

Send article to Kindle

To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

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

Send article to Dropbox

To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

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

Send article to Google Drive

To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

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

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests

Do you have any conflicting interests? *