Theophylline dosing and pharmacokinetics for renal protection in neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia.
Aminophylline
/ administration & dosage
Birth Weight
Creatinine
/ blood
Dose-Response Relationship, Drug
Female
Humans
Hypothermia, Induced
/ adverse effects
Hypoxia-Ischemia, Brain
/ complications
Infant, Newborn
Infant, Premature
Kidney
/ drug effects
Male
Monte Carlo Method
Pharmacokinetics
Prospective Studies
Retrospective Studies
Theophylline
/ administration & dosage
Journal
Pediatric research
ISSN: 1530-0447
Titre abrégé: Pediatr Res
Pays: United States
ID NLM: 0100714
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
30
06
2020
accepted:
13
08
2020
revised:
10
08
2020
pubmed:
13
9
2020
medline:
6
11
2021
entrez:
12
9
2020
Statut:
ppublish
Résumé
Theophylline, a non-selective adenosine receptor antagonist, improves renal perfusion in the setting of hypoxia-ischemia and may offer therapeutic benefit in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of theophylline in this population to guide dosing strategies. A population pharmacokinetic analysis was performed in 22 neonates with HIE undergoing hypothermia who were part of a prospective study or retrospective chart review. Aminophylline (intravenous salt form of theophylline) was given per institutional standard of care for low urine output and/or rising serum creatinine (5 mg/kg intravenous (i.v.) load then 1.8 mg/kg i.v. q6h). The ability of different dosing regimens to achieve target concentrations (4-10 mg/L) associated with clinical response was examined. Birth weight was a significant predictor of theophylline clearance and volume of distribution (p < 0.05). The median half-life was 39.5 h (range 27.2-50.4). An aminophylline loading dose of 7 mg/kg followed by 1.6 mg/kg q12h was predicted to achieve target concentrations in 84% of simulated neonates. In neonates with HIE undergoing hypothermia, theophylline clearance was low with a 50% longer half-life compared to full-term normothermic neonates without HIE. Dosing strategies need to consider the unique pharmacokinetic needs of this population. Theophylline is a potential renal-protective therapy in neonates with HIE undergoing therapeutic hypothermia; however, the pharmacokinetics and dose needs in this population are not known. Theophylline clearance was low in neonates with HIE undergoing therapeutic hypothermia with a 50% longer half-life compared to full-term normothermic neonates without HIE. As theophylline is advanced in clinical development, dosing strategies will need to consider the unique pharmacokinetic needs of neonates with HIE undergoing therapeutic hypothermia.
Sections du résumé
BACKGROUND
Theophylline, a non-selective adenosine receptor antagonist, improves renal perfusion in the setting of hypoxia-ischemia and may offer therapeutic benefit in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of theophylline in this population to guide dosing strategies.
METHODS
A population pharmacokinetic analysis was performed in 22 neonates with HIE undergoing hypothermia who were part of a prospective study or retrospective chart review. Aminophylline (intravenous salt form of theophylline) was given per institutional standard of care for low urine output and/or rising serum creatinine (5 mg/kg intravenous (i.v.) load then 1.8 mg/kg i.v. q6h). The ability of different dosing regimens to achieve target concentrations (4-10 mg/L) associated with clinical response was examined.
RESULTS
Birth weight was a significant predictor of theophylline clearance and volume of distribution (p < 0.05). The median half-life was 39.5 h (range 27.2-50.4). An aminophylline loading dose of 7 mg/kg followed by 1.6 mg/kg q12h was predicted to achieve target concentrations in 84% of simulated neonates.
CONCLUSIONS
In neonates with HIE undergoing hypothermia, theophylline clearance was low with a 50% longer half-life compared to full-term normothermic neonates without HIE. Dosing strategies need to consider the unique pharmacokinetic needs of this population.
IMPACT
Theophylline is a potential renal-protective therapy in neonates with HIE undergoing therapeutic hypothermia; however, the pharmacokinetics and dose needs in this population are not known. Theophylline clearance was low in neonates with HIE undergoing therapeutic hypothermia with a 50% longer half-life compared to full-term normothermic neonates without HIE. As theophylline is advanced in clinical development, dosing strategies will need to consider the unique pharmacokinetic needs of neonates with HIE undergoing therapeutic hypothermia.
Identifiants
pubmed: 32919393
doi: 10.1038/s41390-020-01140-8
pii: 10.1038/s41390-020-01140-8
pmc: PMC7704857
mid: NIHMS1623470
doi:
Substances chimiques
Aminophylline
27Y3KJK423
Creatinine
AYI8EX34EU
Theophylline
C137DTR5RG
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
871-877Subventions
Organisme : NICHD NIH HHS
ID : K23 HD079557
Pays : United States
Références
Selewski, D. T., Jordan, B. K., Askenazi, D. J., Dechert, R. E. & Sarkar, S. Acute kidney injury in asphyxiated newborns treated with therapeutic hypothermia. J. Pediatr. 162, 725–729.e1 (2013).
pubmed: 23149172
Kirkley, M. J. et al. Acute kidney injury in neonatal encephalopathy: an evaluation of the AWAKEN database. Pediatr. Nephrol. 34, 169–176 (2019).
pubmed: 30155763
Gupta, C., Massaro, A. N. & Ray, P. E. A new approach to define acute kidney injury in term newborns with hypoxic ischemic encephalopathy. Pediatr. Nephrol. 31, 1167–1178 (2016).
pubmed: 26857710
pmcid: 4882244
Gouyon, J. B. & Guignard, J. P. Theophylline prevents the hypoxemia-induced renal hemodynamic changes in rabbits. Kidney Int. 33, 1078–1083 (1988).
pubmed: 3404810
Osswald, H., Gleiter, C. & Mühlbauer, B. Therapeutic use of theophylline to antagonize renal effects of adenosine. Clin. Nephrol. 43(Suppl. 1), S33–S37 (1995).
pubmed: 7781203
Jenik, A. G. et al. A randomized, double-blind, placebo-controlled trial of the effects of prophylactic theophylline on renal function in term neonates with perinatal asphyxia. Pediatrics 105, E45 (2000).
pubmed: 10742366
Bakr, A. F. Prophylactic theophylline to prevent renal dysfunction in newborns exposed to perinatal asphyxia—a study in a developing country. Pediatr. Nephrol. 20, 1249–1252 (2005).
pubmed: 15947981
Bhat, M. A., Shah, Z. A., Makhdoomi, M. S. & Mufti, M. H. Theophylline for renal function in term neonates with perinatal asphyxia: a randomized, placebo-controlled trial. J. Pediatr. 149, 180–184 (2006).
pubmed: 16887430
Eslami, Z., Shajari, A., Kheirandish, M. & Heidary, A. Theophylline for prevention of kidney dysfunction in neonates with severe asphyxia. Iran. J. Kidney Dis. 3, 222–226 (2009).
pubmed: 19841526
Raina, A., Pandita, A., Harish, R., Yachha, M. & Jamwal, A. Treating perinatal asphyxia with theophylline at birth helps to reduce the severity of renal dysfunction in term neonates. Acta Paediatr. 105, e448–e451 (2016).
pubmed: 27173369
Saboute, M. et al. Effect of aminophylline in preventing renal dysfunction among neonates with prenatal asphyxia: a clinical trial. Arch. Iran. Med. 23, 312–318 (2020).
pubmed: 32383615
Chock, V. Y., Cho, S.-H. & Frymoyer, A. Aminophylline for renal protection in neonatal hypoxic–ischemic encephalopathy in the era of therapeutic hypothermia. Pediatr. Res. (2020). [Online ahead of print].
Hospira, Inc. FDA package insert aminophylline (aminophylline injection, solution) (2009).
Lowry, J. A., Jarrett, R. V., Wasserman, G., Pettett, G. & Kauffman, R. E. Theophylline toxicokinetics in premature newborns. Arch. Pediatr. Adolesc. Med. 155, 934–939 (2001).
pubmed: 11483122
Zanelli, S., Buck, M. & Fairchild, K. Physiologic and pharmacologic considerations for hypothermia therapy in neonates. J. Perinatol. 31, 377–386 (2011).
pubmed: 21183927
O’Dea, M. et al. Management of multi organ dysfunction in neonatal encephalopathy. Front. Pediatr. 8, 239 (2020).
pubmed: 32500050
pmcid: 7243796
Frymoyer, A., Meng, L., Bonifacio, S. L., Verotta, D. & Guglielmo, B. J. Gentamicin pharmacokinetics and dosing in neonates with hypoxic ischemic encephalopathy receiving hypothermia. Pharmacotherapy 33, 718–726 (2013).
pubmed: 23553582
pmcid: 3700641
Frymoyer, A. et al. Decreased morphine clearance in neonates with hypoxic ischemic encephalopathy receiving hypothermia. J. Clin. Pharm. 57, 64–76 (2017).
Welzing, L. et al. Disposition of midazolam in asphyxiated neonates receiving therapeutic hypothermia—a pilot study. Klin. Padiatr. 225, 398–404 (2013).
pubmed: 24288267
Gal, P., Toback, J., Erkan, N. V. & Boer, H. R. The influence of asphyxia on phenobarbital dosing requirements in neonates. Dev. Pharm. Ther. 7, 145–152 (1984).
Shankaran, S. et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N. Engl. J. Med. 353, 1574–1584 (2005).
pubmed: 16221780
Frymoyer, A., Juul, S. E., Massaro, A. N., Bammler, T. K. & Wu, Y. W. High-dose erythropoietin population pharmacokinetics in neonates with hypoxic-ischemic encephalopathy receiving hypothermia. Pediatr. Res. 81, 865–872 (2017).
pubmed: 28099423
pmcid: 5476365
Anderson, B. J. & Holford, N. H. G. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu. Rev. Pharm. Toxicol. 48, 303–332 (2008).
Jetton, J. G. et al. Incidence and outcomes of neonatal acute kidney injury (AWAKEN): a multicentre, multinational, observational cohort study. Lancet Child Adolesc. Health 1, 184–194 (2017).
pubmed: 29732396
pmcid: 5933049
Hinderling, P. H. Red blood cells: a neglected compartment in pharmacokinetics and pharmacodynamics. Pharm. Rev. 49, 279–295 (1997).
pubmed: 9311024
Mazkereth, R. et al. Effects of theophylline on renal function in premature infants. Am. J. Perinatol. 14, 45–49 (1997).
pubmed: 9259896
Tamburro, R. F. et al. A prospective assessment of the effect of aminophylline therapy on urine output and inflammation in critically ill children. Front. Pediatr. 2, 59 (2014).
pubmed: 24971305
pmcid: 4053781
Lynch, B. A. et al. Low-dose aminophylline for the treatment of neonatal non-oliguric renal failure-case series and review of the literature. J. Pediatr. Pharm. Ther. 13, 80–87 (2008).
Dai, B. et al. Effect of theophylline on prevention of contrast-induced acute kidney injury: a meta-analysis of randomized controlled trials. Am. J. Kidney Dis. 60, 360–370 (2012).
pubmed: 22516682
Axelrod, D. M. et al. Initial experience using aminophylline to improve renal dysfunction in the pediatric cardiovascular ICU. Pediatr. Crit. Care Med. 15, 21–27 (2014).
pubmed: 24212284
Bell, M., Jackson, E., Mi, Z., McCombs, J. & Carcillo, J. Low-dose theophylline increases urine output in diuretic-dependent critically ill children. Intens. Care Med. 24, 1099–1105 (1998).
Brendel, K., Comets, E., Laffont, C. & Mentré, F. Evaluation of different tests based on observations for external model evaluation of population analyses. J. Pharmacokinet. Pharmacodyn. 37, 49–65 (2010).
pubmed: 20033477
Comets, E., Brendel, K. & Mentré, F. Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R. Comput. Methods Prog. Biomed. 90, 154–166 (2008).
van den Broek, M. P. H. et al. Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach. Clin. Pharmacokinet. 51, 671–679 (2012).
pubmed: 23018530
Gilman, J. T., Gal, P., Levine, R. S., Hersh, C. B. & Erkan, N. V. Factors influencing theophylline disposition in 179 newborns. Ther. Drug Monit. 8, 4–10 (1986).
pubmed: 3961896
Gal, P., Boer, H. R., Toback, J., Wells, T. J. & Erkan, N. V. Effect of asphyxia on theophylline clearance in newborns. South Med. J. 75, 836–838 (1982).
pubmed: 7089654
Moore, E. S., Faix, R. G., Banagale, R. C. & Grasela, T. H. The population pharmacokinetics of theophylline in neonates and young infants. J. Pharmacokinet. Biopharm. 17, 47–66 (1989).
pubmed: 2715932
Aranda, J. V., Sitar, D. S., Parsons, W. D., Loughnan, P. M. & Neims, A. H. Pharmacokinetic aspects of theophylline in premature newborns. N. Engl. J. Med. 295, 413–416 (1976).
pubmed: 934239
du Preez, M. J., Botha, J. H., McFadyen, M. L. & Holford, N. H. The pharmacokinetics of theophylline in premature neonates during the first few days after birth. Ther. Drug Monit. 21, 598–603 (1999).
pubmed: 10604818
Fredholm, B. B. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ. 14, 1315–1323 (2007).
pubmed: 17396131
Hansen, P. B. et al. Vasoconstrictor and vasodilator effects of adenosine in the mouse kidney due to preferential activation of A1 or A2 adenosine receptors. J. Pharm. Exp. Ther. 315, 1150–1157 (2005).
Kim, S.-A. et al. Structure-activity relationships at human and rat A2B adenosine receptors of xanthine derivatives substituted at the 1-, 3-, 7-, and 8-positions. J. Med. Chem. 45, 2131–2138 (2002).
pubmed: 12014951
pmcid: 6927247
Klotz, K. N. et al. Comparative pharmacology of human adenosine receptor subtypes—characterization of stably transfected receptors in CHO cells. Naunyn Schmiedebergs Arch. Pharm. 357, 1–9 (1998).
Jacobson, K. A., Ijzerman, A. P. & Linden, J. 1,3-Dialkylxanthine derivatives having high potency as antagonists at human A2B adenosine receptors. Drug Dev. Res. 47, 45–53 (1999).
Favié, L. M. A. et al. Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia. PLoS ONE 14, e0211910 (2019).
pubmed: 30763356
pmcid: 6375702
Bijleveld, Y. A. et al. Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia. Br. J. Clin. Pharm. 81, 1067–1077 (2016).
Clavijo, C. F. et al. A sensitive assay for the quantification of morphine and its active metabolites in human plasma and dried blood spots using high-performance liquid chromatography-tandem mass spectrometry. Anal. Bioanal. Chem. 400, 715–728 (2011).
pubmed: 21400080
Basu, R. K. Dynamic biomarker assessment: a diagnostic paradigm to match the AKI syndrome. Front. Pediatr. 7, 535 (2019).
pubmed: 32039106