Therapeutic drug monitoring of levetiracetam in newborns

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Abstract

Neonatal seizures in full-term and preterm infants represent a common neurological syndrome. Levetiracetam (LEV) is one of the new and widely prescribed second- or third-line antiepileptic drug for the treatment of seizures. Routine therapeutic drug monitoring of LEV was not recommended due to its almost ideal pharmacokinetic profile: linear pharmacokinetics, predictable dose-concentration relationship, wide therapeutic index, favourable safety profile, and unlikely clinically significant drug-drug pharmacokinetic interactions.

In newborns, drug pharmacokinetics may be under the influence of maturation process. LEV pharmacokinetics in newborns appears to be age (gestational, postnatal) dependent and highly variable within the age ranges. These aspects make therapeutic drug monitoring a useful procedure for therapy optimization in this specific patient population.

In population modeling based on therapeutic drug monitoring and nonlinear mixed effects models, covariates were found that should significantly affect the LEV clearance and volume of distribution in newborns — creatinine clearance and total body weight. Using of these regression equations can help to adjust the LEV doses without the patient's measured concentration data. But the significant magnitudes of the interindividual variability remaining in these final regression models justify the need for therapeutic drug monitoring and Bayesian adaptive control for personalization of LEV dosage regimens in neonates.

About the authors

Irina B. Bondareva

Peoples' Friendship University of Russia

Author for correspondence.
Email: i_bomdareva@yahoo.com
Россия, Moscow

Marina A. Ivzhits

Peoples' Friendship University of Russia; City Clinical Hospital No.24

Email: i_bomdareva@yahoo.com
Россия, Moscow

Sergey K. Zyryanov

Peoples' Friendship University of Russia; City Clinical Hospital No.24

Email: i_bomdareva@yahoo.com
Россия, Moscow

Mikhail S. Chenkurov

Peoples' Friendship University of Russia

Email: i_bomdareva@yahoo.com
Россия, Moscow

References

  1. Tulloch J.K., Carr R.R., Ensom M.H. A systematic review of the pharmacokinetics of antiepileptic drugs in neonates with refractory seizures. J Pediatr Pharmacol Ther 2012; 17: 31–44. doi: 10.5863/1551-6776-17.1.31. PMID: 23118657.
  2. Bashmakova N.V., Kraeva O.A, Kostousova E.V. et al. [Features of bioelectric activity of the brain in premature newborns in the neonatal period]. Lechenie i profilaktika 2017; 7(4): 24–30. (In Russ.)
  3. Volpe J.J. Neonatal seizures: current concepts and revised classification. Pediatrics 1989; 84: 422–428. PMID: 2671912.
  4. Ponyatishin A.E., Pal'chik A.B., Berezin V.N.,Parshina V.L. [Convulsions on newborns. Set, controversial and unresolved issues]. Uchenye zapiski SPBGMU im. akad. I.P. Pavlova 2010; (4): 7–15. (In Russ.)
  5. Terent'eva K.A., Haletskaya O.V., Zapevalova T.A [Clinical and etiological characteristics of neonatal seizures]. Meditsinskiy al'manah 2013; (6): 114–116. (In Russ.)
  6. Sirotina Z.V. [Hypoxic and ischemic lesions of the CNS in newborns (clinical lecture)]. Zdravoohranenie Dal'nego Vostoka 2017; (4): 65–74. (In Russ.)
  7. Painter M.J., Scher M.S., Stein A.D. et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999; 341: 485–489. doi: 10.1056/NEJM199908123410704. PMID: 10441604.
  8. Favrais G., Ursino M., Mouchel C. et al. Levetiracetam optimal dose-finding as first-line treatment for neonatal seizures occurring in the context of hypoxic-ischaemic encephalopathy (LEVNEONAT-1): study protocol of a phase II trial. BMJ Open 2019; 9: e022739. doi: 10.1136/bmjopen-2018-022739. PMID: 30679288.
  9. Springer C., Nappe T.M. Anticonvulsants toxicity. Treasure Island; 2019. PMID: 30725891.
  10. Klitgaard H.,Verdru P. Levetiracetam: the first SV2A ligand for the treatment of epilepsy. Exp Opin Drug Discov 2007; 2: 1537–1545. doi: 10.1517/17460441.2.11.1537. PMID: 23484603.
  11. Muhin K.Yu., Freydkova N.V., Glukhova L.Yu. et al. [Juvenile myoclonic epilepsy: focus on the effectiveness of therapy and the frequency of relapses according to prolonged follow-up]. Russkiy zhurnal detskoy nevrologii 2015; 10(4): 7–16. (In Russ.)
  12. Khan O., Chang E., Cipriani C. et al. Use of intravenous levetiracetam for management of acute seizures in neonates. Pediatr Neurol 2011; 44: 265–269. doi: 10.1016/j.pediatrneurol.2010.11.00. PMID: 21397167.
  13. Mruk A.L., Garlitz K.L., Leung N.R. Levetiracetam in neonatal seizures: a review. J Pediatr Pharmacol Ther 2015; 20: 76–89. doi: 10.5863/1551-6776-20.2.76. PMID: 25964725.
  14. Yau M.L., Fung E.L, Ng P.C. Response of levetiracetam in neonatal seizures. World J Clin Pediatr 2015; 4: 45–49. doi: 10.5409/wjcp.v4.i3.45. PMID: 26261766.
  15. Falsaperla R., Vitaliti G., Mauceri L. et al. Levetiracetam in neonatal seizures as first line treatment: a prospective study. J Pediatr Neurosci 2017; 12: 24–28. doi: 10.4103/jpn.JPN_172_16. PMID: 28553374.
  16. Ramantani G., Ikonomidou C., Walter B. et al. Levetiracetam: safety and efficacy in neonatal seizures. Eur J Paediatr Neurol 2011; 15: Р. 1–7. doi: 10.1016/j.ejpn.2010.10.003. PMID: 21094062.
  17. Shoemaker M., Rotenberg J. Levetiracetam for the treatment of neonatal seizures. J Child Neurol 2007; 22: 95–98. doi: 10.1177/0883073807299973. PMID: 17608315.
  18. Patsalos P.N. Pharmacokinetics profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 2000; 85: 77–85. doi: 10.1016/S0163-7258(99)00052-2. PMID: 10722121.
  19. Patsalos P.N. Clinical pharmacokinetics of levetiracetam. Clin Pharmacokinet 2004; 43: 707–724. doi: 10.2165/00003088-200443110-00002. PMID: 15301575.
  20. Patsalos P.N., Ghattaura S., Ratnaraj N., Sander J.W. In situ metabolism of levetiracetam in blood of patients with epilepsy. Epilepsia 2006; 47: 1818–1821. doi: 10.1111/j.1528-1167.2006.00819. PMID: 24843434.
  21. Patsalos P.N. Levetiracetam: pharmacology and therapeutics in the treatment of epilepsy and other neurological conditions. Rev Contemp Pharmacother 2004; 13: 1–168.
  22. Allegaert K., Lewi L., Naulaers G., Lagae L. Levetiracetam pharmacokinetics in neonates at birth. Epilepsia 2006; 47: 1068–1069. doi: 10.1111/j.1528-1167.2006.00576.x. PMID: 16822254.
  23. Johannessen S.I., Helde G., Brodtkorb E. Levetiracetam concentrations in serum and breast milk at birth and during lactation. Epilepsia 2005; 46: 775–777. doi: 10.1111/j.1528-1167.2005.54804.x. PMID: 15857447.
  24. Ramael S., De Smedt F., Toublanc N. et al. Single-dose bioavailability of levetiracetam intravenous infusion relative to oral tablets and multiple-dose pharmacokinetics and tolerability of levetiracetam intravenous infusion compared with placebo in healthy subjects. Clin Ther 2006; 28: 734–44. doi: 10.1016/j.clinthera.2006.05.004. PMID: 16861095.
  25. Pellock J.M., Glauser T.A., Bebin E.M. et al. Pharmacokinetic study of levetiracetam in children. Epilepsia 2001; 42: 1574–1579. doi: 10.1046/j.1528-1157.2001.41300.x. PMID: 11879369.
  26. Hovinga C.A. Levetiracetam: a novel antiepileptic drug. Pharmacotherapy 2001; 21: 1375–1388. doi: 10.1592/phco.21.17.1375.34432. PMID: 11714211.
  27. Patsalos P.N., Berry D.J., Bourgeois B.F. et al. Antiepileptic drugs — best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 2008; 49: 1239–1276. doi: 10.1111/j.1528-1167.2008.01561.x. PMID: 18397299.
  28. Patsalos P.N. Anti-epileptic drug interactions. A clinical guide. Guildford, 2005.
  29. Hirsch L.J., Arif H., Buchsbaum R. et al. Effect of age and comedication on levetiracetam pharmacokinetics and tolerability. Epilepsia 2007; 48: 1351–1359. doi: 10.1111/j.1528-1167.2007.01043.x. PMID: 17573925.
  30. Perucca E., Gidal B.E., Baltès E. Effects of antiepileptic comedication on levetiracetam pharmacokinetics: a pooled analysis of data from randomized adjunctive therapy trials. Epilepsy Res 2003; 53: 47–56. doi: 10.1016/S0920-1211(02)00250-4. PMID: 12576167.
  31. Perucca E., Gidal B.E., Ledent E., Baltes E. Levetiracetam does not interact with other antiepileptic drugs. Epilepsia 2000; 41S: 254.
  32. May T.W., Rambeck B., Jurgens U. Serum concentrations of levetiracetam in epileptic patients: the influence of dose and co-medication. Ther Drug Monit 2003; 25: 690–699. doi: 10.1097/00007691-200312000-00007. PMID: 14639055.
  33. Jarvie D., Mahmoud S.H. Therapeutic drug monitoring of levetiracetam in select populations. J Pharm Pharm Sci 2018; 21: 149s–176s. doi: 10.18433/jpps30081. PMID: 30096051.
  34. Barrueto F.Jr., Williams K., Howland M.A. et al. A case of levetiracetam (Keppra) poisoning with clinical and toxicokinetic data. J Toxicol Clin Toxicol 2002; 40: 881–884. doi: 10.1081/clt-120016959. PMID: 12507057.
  35. Chayasirisobhon S., Chayasirisobhon W.V., Tsay C.C. Acute levetiracetam overdose presented with mild adverse events. Acta Neurol 2010; 19: 292–295. doi: 10.1081/clt-120016959. PMID: 21210332.
  36. Page C.B., Mostafa A., Saiao A. et al. Cardiovascular toxicity with levetiracetam overdose. Clin Toxicol (Phila) 2016; 54: 152–154. doi: 10.3109/15563650.2015.1115054. PMID: 26795744.
  37. Patsalos P.N., Berry D.J., Bourgeois B.F. et al. Antiepileptic drugs — best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 2008; 49: 1239–1276. doi: 10.1111/j.1528-1167.2008.01561.x. PMID: 18397299.
  38. Jacob S., Nair A.B. An updated overview on therapeutic drug monitoring of recent antiepileptic drugs. Drugs RD 2016; 16: 303–316. doi: 10.1007/s40268-016-0148-6. PMID: 27766590.
  39. Bondareva I. Individualizing antiepileptic therapy for patients. In: R.W. Jelliffe, M. Neely (eds.) Individualized Drug Therapy for Patients: Basic Foundations, Relevant Software and Clinical Applications. Elsevier, 2017: 327–372.
  40. Krasowski M.D. Therapeutic drug monitoring of the newer anti-epilepsy medications. Pharmaceuticals (Basel) 2010; 3: 1909–1935. doi: 10.3390/ph3061909. PMID: 206402233.
  41. Leppik I.E., Rarick J.O., Walczak T.S. et al. Effective levetiracetam doses and serum concentrations: Age effects. Epilepsia 2002; 43: 240. doi: 10.1046/j.1528-1157.2002.33301.x.11906508.
  42. Jacob S., Nair A.B. An updated overview on therapeutic drug monitoring of recent antiepileptic drugs. Drugs RD 2016; 16: 303–316. doi: 10.1007/s40268-016-0148-6. PMID: 27766590.
  43. Johannessen S.I., Battino D., Berry D.J. et al. Therapeutic drug monitoring of the newer antiepileptic drugs. Ther Drug Monit 2003; 25: 347–363. doi: 10.1097/00007691-200306000-00016. PMID: 12766564.
  44. Chhun S., Jullien V., Rey E. et al. Population pharmacokinetics of levetiracetam and dosing recommendation in children with epilepsy. Epilepsia 2009; 50: 1150–1157. doi: 10.1111/j.1528-1167.2008.01974.x. PMID: 19175400.
  45. Reimers A., Berg J.A., Burns M.L. et al. Reference ranges for antiepileptic drugs revisited: a practical approach to establish national guidelines Drug Des Dev Ther 2018: 12: 271–280. doi: 10.2147/DDDT.S154388. PMID: 29467570.
  46. Stepanova D., Beran R.G. Measurement of levetiracetam drug levels to assist with seizure control and monitoring of drug interactions with other antiepileptic medications (AEMs). Seizure 2014; 23: 371–376. doi: 10.1016/j.seizure.2014.02.003. PMID: 24630809.
  47. Mathew B.S., Fleming D.H., Thomas M. et al. An initial experience with therapeutic drug monitoring of levetiracetam as reported from a pediatric clinical setting in India. Neurol India 2012; 60: 146–149. doi: 10.4103/0028-3886.96382. PMID: 22626693.
  48. Iwasaki T., Toki T., Nonoda Y., Ishii M. The efficacy of levetiracetam for focal seizures and its blood levels in children. Brain Dev 2015; 37: 773–779. doi: 10.1016/j.braindev.2014.11.008. PMID: 25579248.
  49. Mink S., Muroi C., Seule M. et al. Levetiracetam compared to valproic acid: plasma concentration levels, adverse effects and interactions in aneurysmal subarachnoid hemorrhage. Clin Neurol Neurosurg 2011; 113: 644–648. doi: 10.1016/j.clineuro.2011.05.007. PMID: 21703756.
  50. Ng Y.T., Hastriter E.V., Cardenas J.F. et al. Intravenous levetiracetam in children with seizures: a prospective safety study. J Child Neurol 2010; 25: 551–555. doi: 10.1177/0883073809348795. PMID: 20413804.
  51. Sheinberg R., Heyman E., Dagan Z. et al. Correlation between efficacy of levetiracetam and serum levels among children with refractory epilepsy. Pediatr Neurol 2015; 52: 624–628. DOI: 10.1016/j. pediatrneurol.2015.01.012. PMID: 25791893.
  52. Radtke R.A. Pharmacokinetics of levetiracetam. Epilepsia 2001; 42: 24–27. doi: 10.1046/j.1528-1157.2001.0420s4024.x. PMID: 11564121.
  53. Kearns G.L., Abdel-Rahman S.M., Alander S.W. et al. Developmental pharmacology: drug disposition, action, and therapy in infants and children. N Engl J Med 2003; 349: 1157–1167. doi: 10.1056/NEJMra035092. PMID: 13679531.
  54. Allegaert K., Verbesselt R., van den Anker J.N. et al. Developmental pharmacology: since neonates are not just small adults. Acta Clin Belg 2008; 63: 16–24. doi: 10.1179/acb.2008.003. PMID: 18386761.
  55. Fanos V., Yurdakök M. Personalized neonatal medicine. J Matern Fetal Neonatal Med 2010; 23: 4–6. doi: 10.3109/14767058.2010.513103. PMID: 20822336.
  56. Smits A., Kulo A., de Hoon J.N., Allegaert K. Pharmacokinetics of drugs in neonates: pattern recognition beyond compound specific observations. Curr Pharm Des 2012; 18: 3119–3146. doi: 10.2174/1381612811209023119. PMID: 22564304.
  57. Spagnoli C., Pisani F. The independent role of neonatal seizures in epilepsy and other long-term neurological outcomes. Dev Med Child Neurol 2019 61: 624. doi: 10.1111/dmcn.14197. PMID: 30762238.
  58. Turner M.A. Neonatal drug development. Early Hum Dev 2011; 87: 763–768. doi: 10.1016/j.earlhumdev.2011.08.014. PMID: 21925812.
  59. Van den Anker J.N. Managing drugs safely. Semin Fetal Neonatal Med 2005; 10: 73–81. doi: 10.1016/j.siny.2004.09.005. PMID: 15698972.
  60. Broussard L. Small size, big risk: preventing neonatal and pediatric medication errors. Nurs Womens Health 2010; 14: 405–408. doi: 10.1111/j.1751-486X.2010.01580.x. PMID: 20955530.
  61. Lins R.L., Otoul C., De Smedt F. et al. Comparison of plasma and saliva concentrations of levetiracetam following administration orally as a tablet and as a solution in healthy adult volunteers. Int J Clin Pharmacol Ther 2007; 45: 47–54. doi: 10.5414/cpp45047. PMID: 17256450.
  62. Grim S.A., Ryan M., Miles M.V. et al. Correlation of levetiracetam concentrations between serum and plasma. Ther Drug Monit 2003; 25: 61–66. doi: 10.1097/00007691-200302000-00009. PMID: 12548146.
  63. Patsalos P.N., Berry D.J. Therapeutic drug monitoring of antiepileptic drugs by use of saliva. Ther Drug Monit 2013; 35: 4–29. doi: 10.1097/FTD.0b013e31827c11e7. PMID: 23288091.
  64. Weinstock A., Ruiz M., Gerard D. et al. Prospective open-label, single-arm, multicenter, safety, tolerability, and pharmacokinetic studies of intravenous levetiracetam in children with epilepsy. J Child Neurol 2013; 28: 1423–1429. doi: 10.1177/0883073813480241. PMID: 23533164.
  65. Mian P., Flint R.B., Tibboel D. et al. Therapeutic drug monitoring in neonates: what makes them unique? Curr Pharm Des 2017; 23: 5790–5800. doi: 10.2174/1381612823666170926143820. PMID: 28950825.
  66. Allegaert K., Rayyan M., Vanhaesebrouck S. et al. Developmental pharmacokinetics in neonates. Expert Rev Clin Pharmacol 2008; 1: 415–428. doi: 10.1586/17512433.1.3.415. PMID: 24422695.
  67. Discussion paper on the impact of renal immaturity when investigating medicinal products intended for paediatric use, EMA, December 2004. URL: https://www.ema.europa.eu/en/documents/scientific-guideline/discussion-paper-impact-renal-immaturity-when-investigating-medicinal-products-intended-paediatric_en.pdf
  68. Hoseini R., Otukesh H., Rahimzadeh N., Hosseini S. Glomerular function in neonates. Iran J Kidney Dis 2012; 6: 166–172. PMID: 22555478.
  69. Beal S.L., Sheiner L.B. NONMEM Users Guide. Part I. Users Basic Guide. San Francisco, 1989.
  70. Jelliffe R.W., Schumitzky A., Van Guilder M., Jiang F. User Manual for Version 10.7 of USC*PACK Collection of PC Programs. Los Angeles, 1996.
  71. Allegaert K., van de Velde M., van den Anker J. Neonatal clinical pharmacology. Paediatr Anaesth 2014; 24: 30–38. doi: 10.1111/pan.12176. PMID: 23617305.
  72. Smits A., De Cock R.F., Allegaert K. et al. Prospective evaluation of a model-based dosing regimen for amikacin in preterm and term neonates in clinical practice. Antimicrob Agents Chemother 2015; 59: 6344–6351. doi: 10.1128/AAC.01157-15. PMID: 26248375.
  73. Young T.E. Therapeutic drug monitoring — the appropriate use of drug level measurement in the care of the neonate. Clin Perinatol 2012; 39: 25–31. doi: 10.1016/j.clp.2011.12.009. PMID: 22341534.
  74. Pauwels S., Allegaert K. Therapeutic drug monitoring in neonates. Arch Dis Child 2016; 101: 377–381. doi: 10.1136/archdischild-2013-305309. PMID: 26803050.
  75. Merhar S.L., Schibler K.R., Sherwin C.M. et al. Pharmacokinetics of levetiracetam in neonates with seizures. J Pediatr 2011; 159: 152–154. doi: 10.1016/j.jpeds.2011.03.057. PMID: 21592494.
  76. Sharpe C.M., Capparelli E.V., Mower A. et al. A seven-day study of the pharmacokinetics of intravenous levetiracetam in neonates: marked changes in pharmacokinetics occur during the first week of life. Pediatr Res 2012; 72: 43–49. doi: 10.1038/pr.2012.51. PMID: 22495532.
  77. Lima-Rogel V., López-López E.J., Medellín-Garibay S.E. et al. Population pharmacokinetics of levetiracetam in neonates with seizures. J Clin Pharm Ther 2017; 1–8. doi: 10.1111/jcpt.12658. PMID: 29265480.
  78. Schwartz G.J., Brion L.P., Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am 1987; 34: 571–590. PMID: 3588043.
  79. De Cock R.F., Piana C., Krekels E.H. et al. The role of population PK-PD modelling in paediatric clinical research. Eur J Clin Pharmacol 2011; 67(Suppl 1): 5–16. doi: 10.1007/s00228-009-0782-9. PMID: 20340012.
  80. Smits A., Kulo A., de Hoon J.N., Allegaert K. Pharmacokinetics of drugs in neonates: pattern recognition beyond compound specific observations. Curr Pharm Des 2012; 18: 3119–3146. doi: 10.2174/1381612811209023119. PMID: 22564304.
  81. Sergienko V.I., Jelliffe R., Bondareva I.B. [Applied pharmacokinetics: guidelines and clinical application]. Moscow, 2003. (In Russ.)
  82. Pons G., Tréluyer J.M., Dimet J. et al. Potential benefit of Bayesian forecasting for therapeutic drug monitoring in neonates. Ther Drug Monit 2002; 24: 9–14. doi: 10.1097/00007691-200202000-00002. PMID: 11805715.
  83. Eliasson E., Lindh J.D., Malmstrom R.E. et al. Therapeutic drug monitoring for tomorrow. Eur J Clin Pharmacol 2013; 69 Suppl 1: 25–32. doi: 10.1007/s00228-013-1504-x. PMID: 23640185.
  84. Jelliffe R.W., Neely M. (eds.) Individualized Drug Therapy for Patients: Basic Foundations, Relevant Software and Clinical Applications. Elsevier, 2017.

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