PK and Safety of Caffeine in Neonates With Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia

Summary

A phase 1 study investigating the tolerability and pharmacokinetics of caffeine citrate in neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia. This study is an essential first step to develop caffeine as a kidney protective medication in this in this vulnerable group of newborns.

Timeline

Start

2024-05-08

Primary completion

2024-05-08

Completion

2024-05-08

Publications

• Background Rumpel J, Spray BJ, Chock VY, Kirkley MJ, Slagle CL, Frymoyer A, Cho SH, Gist KM, Blaszak R, Poindexter B, Courtney SE. Urine Biomarkers for the Assessment of Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia. J Pediatr. 2022 Feb;241:133-140.e3. doi: 10.1016/j.jpeds.2021.08.090. Epub 2021 Sep 20.
• Background Selewski DT, Jordan BK, Askenazi DJ, Dechert RE, Sarkar S. Acute kidney injury in asphyxiated newborns treated with therapeutic hypothermia. J Pediatr. 2013 Apr;162(4):725-729.e1. doi: 10.1016/j.jpeds.2012.10.002. Epub 2012 Nov 10.
• Background Kirkley MJ, Boohaker L, Griffin R, Soranno DE, Gien J, Askenazi D, Gist KM; Neonatal Kidney Collaborative (NKC). Acute kidney injury in neonatal encephalopathy: an evaluation of the AWAKEN database. Pediatr Nephrol. 2019 Jan;34(1):169-176. doi: 10.1007/s00467-018-4068-2. Epub 2018 Aug 28.
• Background Jetton JG, Boohaker LJ, Sethi SK, Wazir S, Rohatgi S, Soranno DE, Chishti AS, Woroniecki R, Mammen C, Swanson JR, Sridhar S, Wong CS, Kupferman JC, Griffin RL, Askenazi DJ; Neonatal Kidney Collaborative (NKC). Incidence and outcomes of neonatal acute kidney injury (AWAKEN): a multicentre, multinational, observational cohort study. Lancet Child Adolesc Health. 2017 Nov;1(3):184-194. doi: 10.1016/S2352-4642(17)30069-X.
• Background Cavallin F, Rubin G, Vidal E, Cainelli E, Bonadies L, Suppiej A, Trevisanuto D. Prognostic role of acute kidney injury on long-term outcome in infants with hypoxic-ischemic encephalopathy. Pediatr Nephrol. 2020 Mar;35(3):477-483. doi: 10.1007/s00467-019-04406-4. Epub 2019 Dec 11.
• Background Bhatt GC, Gogia P, Bitzan M, Das RR. Theophylline and aminophylline for prevention of acute kidney injury in neonates and children: a systematic review. Arch Dis Child. 2019 Jul;104(7):670-679. doi: 10.1136/archdischild-2018-315805. Epub 2019 Feb 23.
• Background Chock VY, Cho SH, Frymoyer A. Aminophylline for renal protection in neonatal hypoxic-ischemic encephalopathy in the era of therapeutic hypothermia. Pediatr Res. 2021 Mar;89(4):974-980. doi: 10.1038/s41390-020-0999-y. Epub 2020 Jun 5.
• Background Harer MW, Askenazi DJ, Boohaker LJ, Carmody JB, Griffin RL, Guillet R, Selewski DT, Swanson JR, Charlton JR; Neonatal Kidney Collaborative (NKC). Association Between Early Caffeine Citrate Administration and Risk of Acute Kidney Injury in Preterm Neonates: Results From the AWAKEN Study. JAMA Pediatr. 2018 Jun 4;172(6):e180322. doi: 10.1001/jamapediatrics.2018.0322. Epub 2018 Jun 4.
• Background Aviles-Otero N, Kumar R, Khalsa DD, Green G, Carmody JB. Caffeine exposure and acute kidney injury in premature infants with necrotizing enterocolitis and spontaneous intestinal perforation. Pediatr Nephrol. 2019 Apr;34(4):729-736. doi: 10.1007/s00467-018-4140-y. Epub 2018 Nov 10.
• Background Carmody JB, Harer MW, Denotti AR, Swanson JR, Charlton JR. Caffeine Exposure and Risk of Acute Kidney Injury in a Retrospective Cohort of Very Low Birth Weight Neonates. J Pediatr. 2016 May;172:63-68.e1. doi: 10.1016/j.jpeds.2016.01.051. Epub 2016 Feb 18.
• Background AlGadeeb K, Qaraqei M, Algadeeb R, Faqeehi H, Al-Matary A. Prediction of risk factors and outcomes of neonatal acute kidney injury. J Nephrol. 2021 Oct;34(5):1659-1668. doi: 10.1007/s40620-021-01130-x. Epub 2021 Sep 1.
• Background Dobson NR, Patel RM, Smith PB, Kuehn DR, Clark J, Vyas-Read S, Herring A, Laughon MM, Carlton D, Hunt CE. Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants. J Pediatr. 2014 May;164(5):992-998.e3. doi: 10.1016/j.jpeds.2013.12.025. Epub 2014 Jan 23.
• Background Lee TC, Charles B, Steer P, Flenady V, Shearman A. Population pharmacokinetics of intravenous caffeine in neonates with apnea of prematurity. Clin Pharmacol Ther. 1997 Jun;61(6):628-40. doi: 10.1016/S0009-9236(97)90097-7.
• Background Charles BG, Townsend SR, Steer PA, Flenady VJ, Gray PH, Shearman A. Caffeine citrate treatment for extremely premature infants with apnea: population pharmacokinetics, absolute bioavailability, and implications for therapeutic drug monitoring. Ther Drug Monit. 2008 Dec;30(6):709-16. doi: 10.1097/FTD.0b013e3181898b6f.
• Background Falcao AC, Fernandez de Gatta MM, Delgado Iribarnegaray MF, Santos Buelga D, Garcia MJ, Dominguez-Gil A, Lanao JM. Population pharmacokinetics of caffeine in premature neonates. Eur J Clin Pharmacol. 1997;52(3):211-7. doi: 10.1007/s002280050276.
• Background Thomson AH, Kerr S, Wright S. Population pharmacokinetics of caffeine in neonates and young infants. Ther Drug Monit. 1996 Jun;18(3):245-53. doi: 10.1097/00007691-199606000-00005.
• Background CAFCIT (caffeine citrate) Injection, CAFCIT (caffeine citrate) Oral solution, Package insert. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20793s1lbl.pdf. Accessed October 30, 2021.
• Background Gillot I, Gouyon JB, Guignard JP. Renal effects of caffeine in preterm infants. Biol Neonate. 1990;58(3):133-6. doi: 10.1159/000243252.
• Background Zappitelli M, Ambalavanan N, Askenazi DJ, Moxey-Mims MM, Kimmel PL, Star RA, Abitbol CL, Brophy PD, Hidalgo G, Hanna M, Morgan CM, Raju TNK, Ray P, Reyes-Bou Z, Roushdi A, Goldstein SL. Developing a neonatal acute kidney injury research definition: a report from the NIDDK neonatal AKI workshop. Pediatr Res. 2017 Oct;82(4):569-573. doi: 10.1038/pr.2017.136. Epub 2017 Jul 11. No abstract available.
• Background Echeverri D, Montes FR, Cabrera M, Galan A, Prieto A. Caffeine's Vascular Mechanisms of Action. Int J Vasc Med. 2010;2010:834060. doi: 10.1155/2010/834060. Epub 2010 Aug 25.
• Background Aranda JV, Collinge JM, Zinman R, Watters G. Maturation of caffeine elimination in infancy. Arch Dis Child. 1979 Dec;54(12):946-9. doi: 10.1136/adc.54.12.946.
• Background Aranda JV, Beharry KD. Pharmacokinetics, pharmacodynamics and metabolism of caffeine in newborns. Semin Fetal Neonatal Med. 2020 Dec;25(6):101183. doi: 10.1016/j.siny.2020.101183. Epub 2020 Nov 26.
• Background Zanelli S, Buck M, Fairchild K. Physiologic and pharmacologic considerations for hypothermia therapy in neonates. J Perinatol. 2011 Jun;31(6):377-86. doi: 10.1038/jp.2010.146. Epub 2010 Dec 23.
• Background Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W; Caffeine for Apnea of Prematurity Trial Group. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006 May 18;354(20):2112-21. doi: 10.1056/NEJMoa054065.
• Background Frymoyer A, Van Meurs KP, Drover DR, Klawitter J, Christians U, Chock VY. Theophylline dosing and pharmacokinetics for renal protection in neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia. Pediatr Res. 2020 Dec;88(6):871-877. doi: 10.1038/s41390-020-01140-8. Epub 2020 Sep 12.
• Background Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W; Caffeine for Apnea of Prematurity Trial Group. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med. 2007 Nov 8;357(19):1893-902. doi: 10.1056/NEJMoa073679.
• Background Schmidt B, Anderson PJ, Doyle LW, Dewey D, Grunau RE, Asztalos EV, Davis PG, Tin W, Moddemann D, Solimano A, Ohlsson A, Barrington KJ, Roberts RS; Caffeine for Apnea of Prematurity (CAP) Trial Investigators. Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity. JAMA. 2012 Jan 18;307(3):275-82. doi: 10.1001/jama.2011.2024.
• Background Schmidt B, Roberts RS, Anderson PJ, Asztalos EV, Costantini L, Davis PG, Dewey D, D'Ilario J, Doyle LW, Grunau RE, Moddemann D, Nelson H, Ohlsson A, Solimano A, Tin W; Caffeine for Apnea of Prematurity (CAP) Trial Group. Academic Performance, Motor Function, and Behavior 11 Years After Neonatal Caffeine Citrate Therapy for Apnea of Prematurity: An 11-Year Follow-up of the CAP Randomized Clinical Trial. JAMA Pediatr. 2017 Jun 1;171(6):564-572. doi: 10.1001/jamapediatrics.2017.0238.
• Background McPherson C, Neil JJ, Tjoeng TH, Pineda R, Inder TE. A pilot randomized trial of high-dose caffeine therapy in preterm infants. Pediatr Res. 2015 Aug;78(2):198-204. doi: 10.1038/pr.2015.72. Epub 2015 Apr 9.
• Background Vesoulis ZA, McPherson C, Neil JJ, Mathur AM, Inder TE. Early High-Dose Caffeine Increases Seizure Burden in Extremely Preterm Neonates: A Preliminary Study. J Caffeine Res. 2016 Sep 1;6(3):101-107. doi: 10.1089/jcr.2016.0012.
• Background Chock VY, Frymoyer A, Yeh CG, Van Meurs KP. Renal Saturation and Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia. J Pediatr. 2018 Sep;200:232-239.e1. doi: 10.1016/j.jpeds.2018.04.076. Epub 2018 Jun 1.
• Background Perera V, Gross AS, McLachlan AJ. Caffeine and paraxanthine HPLC assay for CYP1A2 phenotype assessment using saliva and plasma. Biomed Chromatogr. 2010 Oct;24(10):1136-44. doi: 10.1002/bmc.1419.
• Background Lynch NE, Stevenson NJ, Livingstone V, Mathieson S, Murphy BP, Rennie JM, Boylan GB. The temporal characteristics of seizures in neonatal hypoxic ischemic encephalopathy treated with hypothermia. Seizure. 2015 Dec;33:60-5. doi: 10.1016/j.seizure.2015.10.007. Epub 2015 Oct 23.

Drugs

Indications