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Bottom-up PBPK modeling of phenytoin brain disposition in postpartum newborns after intrauterine dosing

  • Mo’tasem M. Alsmadi EMAIL logo
Published/Copyright: August 8, 2024
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Drug Metabolism and Personalized Therapy
From the journal Drug Metabolism and Personalized Therapy Volume 39 Issue 3

Abstract

Objectives

The antiepileptic phenytoin has a narrow therapeutic window, nonlinear pharmacokinetics, and can cross the placenta causing apathy and jitteriness in postpartum newborns. Further, the sudden decay of phenytoin concentration can cause withdrawal seizures. This work aimed to assess the brain toxic exposure to phenytoin in newborns after transplacental transfer using neonatal saliva-brain correlations.

Methods

The phenytoin dose that the newborn receives transplacentally at birth was estimated using verified physiologically based pharmacokinetic (PBPK) model simulations in third-trimester pregnancy (pregnancy T3). Such doses were used as an input to the newborn PBPK model to estimate the neonatal levels of phenytoin and their correlations in brain extracellular fluid (bECF), plasma, and saliva.

Results

The PBPK model-estimated neonatal plasma and bECF concentrations of phenytoin were below the necessary thresholds for anticonvulsant and toxic effects. The neonatal salivary thresholds for phenytoin anticonvulsant and toxic effects were estimated to be 1.3 and 2.5 mg/L, respectively using the plasma-saliva-bECF correlations established herein.

Conclusions

The salivary TDM of phenytoin can be a more convenient option for avoiding phenytoin brain toxicity in newborns of epileptic mothers. Still, the appropriateness of using the same adult values of phenytoin anticonvulsant and toxic effects for infants needs investigation.

Keywords: neonatal withdrawal seizures; neuroprotection via inhibition of voltage-gated Na+ channels; PBPK modeling; transplacental diffusion of phenytoin
Corresponding author: Mo’tasem M. Alsmadi, PhD, Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science & Technology, P.O.Box 3030, Irbid 22110, Jordan; and Nanotechnology Institute, Jordan University of Science & Technology, Irbid, Jordan; E-mail:

Funding source: This work received no funding

Acknowledgments

The author acknowledges Jordan University of Science and Technology (Irbid, Jordan) for all the facilities and support provided.

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author contributions: The author has accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Competing interests: The author states no conflict of interest.

  5. Research funding: This work received no funding.

  6. Data availability: Not applicable.

References

1. Fisher, RS, Boas, WE, Blume, W, Elger, C, Genton, P, Lee, P, et al.. Epileptic seizures and epilepsy: definitions proposed by the international league against epilepsy (ILAE) and the International Bureau for epilepsy (IBE). Epilepsia 2005;46:470–2. https://doi.org/10.1111/j.0013-9580.2005.66104.x.Search in Google Scholar PubMed

2. Fischer, JH, Patel, TV, Fischer, PA. Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures. Clin Pharmacokinet 2003;42:33–58. https://doi.org/10.2165/00003088-200342010-00002.Search in Google Scholar PubMed

3. Koch, S, Jäger‐Roman, E, Lösche, G, Nau, H, Rating, D, Helge, H. Antiepileptic drug treatment in pregnancy: drug side effects in the neonate and neurological outcome. Acta Paediatr 1996;85:739–46. https://doi.org/10.1111/j.1651-2227.1996.tb14137.x.Search in Google Scholar PubMed

4. Azar, NJ, Wang, L, Song, Y, Abou-Khalil, BW. Temporal pattern of oxcarbazepine and phenytoin withdrawal seizures during epilepsy monitoring. Epilepsy Res 2008;79:78–83. https://doi.org/10.1016/j.eplepsyres.2007.12.014.Search in Google Scholar PubMed

5. Richens, A. Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet 1979;4:153–69. https://doi.org/10.2165/00003088-197904030-00001.Search in Google Scholar PubMed

6. Peterson, GM, McLEAN, S, Aldous, S, Von Witt, R, Millingen, K. Plasma protein binding of phenytoin in 100 epileptic patients. Br J Clin Pharmacol 1982;14:298–300. https://doi.org/10.1111/j.1365-2125.1982.tb01981.x.Search in Google Scholar PubMed PubMed Central

7. Miners, JO, Birkett, DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998;45:525–38. https://doi.org/10.1046/j.1365-2125.1998.00721.x.Search in Google Scholar PubMed PubMed Central

8. Tassaneeyakul, W, Veronese, M, Birkett, D, Doecke, C, McManus, M, Sansom, L, et al.. Co-regulation of phenytoin and tolbutamide metabolism in humans. Br J Clin Pharmacol 1992;34:494.Search in Google Scholar

9. Pade, V, Stavchansky, S. Link between drug absorption solubility and permeability measurements in Caco-2 cells. J Pharm Sci 1998;87:1604–7. https://doi.org/10.1021/js980111k.Search in Google Scholar PubMed

10. Mirkin, BL. Diphenylhydantoin: placental transport, fetallocalization, neonatal metabolism, and possible teratogenic effects. J Pediatr 1971;78:329–37. https://doi.org/10.1016/S0022-3476(71)80025-2.Search in Google Scholar PubMed

11. Rane, A, Garle, M, Borgå, O, Sjöqvist, F. Plasma disappearance of transplacentally transferred diphenylhydantoin in the newborn studied by mass fragmentography. Clin Pharmacol Ther 1974;15:39–45. https://doi.org/10.1002/cpt197415139.Search in Google Scholar PubMed

12. Levine, M, Chang, T. Therapeutic drug monitoring of phenytoin rationale and current status. Clin Pharmacokinet 1990;19:341–58. https://doi.org/10.2165/00003088-199019050-00001.Search in Google Scholar PubMed

13. Abduljalil, K, Pan, X, Pansari, A, Jamei, M, Johnson, TN. A preterm physiologically based pharmacokinetic model. Part I: physiological parameters and model building. Clin Pharmacokinet 2020;59:485–500. https://doi.org/10.1007/s40262-019-00825-6.Search in Google Scholar PubMed

14. Loughnan, PM, Greenwald, A, Purton, WW, Aranda, J, Watters, G, Neims, AH. Pharmacokinetic observations of phenytoin disposition in the newborn and young infant. Arch Dis Child 1977;52:302. https://doi.org/10.1136/adc.52.4.302.Search in Google Scholar PubMed PubMed Central

15. Bauer, LA, Blouin, RA. Phenytoin Michaelis-Menten pharmacokinetics in Caucasian paediatric patients. Clin Pharmacokinet 1983;8:545–9. https://doi.org/10.2165/00003088-198308060-00006.Search in Google Scholar PubMed

16. Batchelor, H, Appleton, R, Hawcutt, DB. Comparing paediatric intravenous phenytoin doses using physiologically based pharmacokinetic (PBPK) modelling software. Seizure 2015;33:8–12. https://doi.org/10.1016/j.seizure.2015.10.006.Search in Google Scholar PubMed

17. Alsmadi, MM, Idkaidek, N. Optimization of drugs pharmacotherapy during pregnancy using physiologically based pharmacokinetic models-an update. Curr Drug Metabol 2018;19:972–8. https://doi.org/10.2174/1389200219666180702104034.Search in Google Scholar PubMed

18. Hutchinson, L, Sinclair, M, Reid, B, Burnett, K, Callan, B. A descriptive systematic review of salivary therapeutic drug monitoring in neonates and infants. Br J Clin Pharmacol 2018;84:1089–108. https://doi.org/10.1111/bcp.13553.Search in Google Scholar PubMed PubMed Central

19. Troupin, A, Friel, P. Anticonvulsant level in saliva, serum, and cerebrospinal fluid. Epilepsia 1975;16:223–7. https://doi.org/10.1111/j.1528-1157.1975.tb06051.x.Search in Google Scholar PubMed

20. Bachmann, K, Forney, RBJr, Voeller, K. Monitoring phenytoin in salivary and plasma ultrafiltrates of pediatric patients. Ther Drug Monit 1983;5:325–9. https://doi.org/10.1097/00007691-198309000-00014.Search in Google Scholar PubMed

21. Mucklow, JC, Bacon, CJ, Hierons, AM, Webb, JK, Rawlins, MD. Monitoring of phenobarbitone and phenytoin therapy in small children by salivary samples. Ther Drug Monit 1981;3:275–7. https://doi.org/10.1097/00007691-198103000-00008.Search in Google Scholar PubMed

22. t Jong, GW, Vulto, AG, de Hoog, M, Schimmel, KJ, Tibboel, D, van den Anker, JN. Unapproved and off-label use of drugs in a children’s hospital. N Engl J Med 2000;343:1125. https://doi.org/10.1056/NEJM200010123431515.Search in Google Scholar PubMed

23. Liu, XI, Momper, JD, Rakhmanina, NY, Green, DJ, Burckart, GJ, Cressey, TR, et al.. Physiologically based pharmacokinetic modeling framework to predict neonatal pharmacokinetics of transplacentally acquired emtricitabine, dolutegravir, and raltegravir. Clin Pharmacokinet 2021;60:795–809. https://doi.org/10.1007/s40262-020-00977-w.Search in Google Scholar PubMed PubMed Central

24. Alsmadi, MM, Idkaidek, N. The analysis of pethidine pharmacokinetics in newborn saliva, plasma, and brain extracellular fluid after prenatal intrauterine exposure from pregnant mothers receiving intramuscular dose using PBPK modeling. Eur J Drug Metab Pharmacokinet 2023;48:281–300. https://doi.org/10.1007/s13318-023-00823-x.Search in Google Scholar PubMed

25. Alsmadi, MM. Evaluating the pharmacokinetics of fentanyl in the brain extracellular fluid, saliva, urine, and plasma of newborns from transplacental exposure from parturient mothers dosed with Epidural fentanyl utilizing PBPK modeling. Eur J Drug Metab Pharmacokinet 2023;48:567–86. https://doi.org/10.1007/s13318-023-00842-8.Search in Google Scholar PubMed

26. Alsmadi, MM. Salivary therapeutic monitoring of methadone toxicity in neonates after transplacental transfer from parturient mothers treated with oral methadone guided by PBPK modeling. Comput Toxicol 2024;29:100296. https://doi.org/10.1016/j.comtox.2023.100296.Search in Google Scholar

27. Polasek, TM, Polak, S, Doogue, MP, Rostami-Hodjegan, A, Miners, JO. Assessment of inter-individual variability in predicted phenytoin clearance. Eur J Clin Pharmacol 2009;65:1203–10. https://doi.org/10.1007/s00228-009-0703-y.Search in Google Scholar PubMed

28. Chiang, P-C, Wong, H. Incorporation of physiologically based pharmacokinetic modeling in the evaluation of solubility requirements for the salt selection process: a case study using phenytoin. AAPS J 2013;15:1109–18. https://doi.org/10.1208/s12248-013-9519-x.Search in Google Scholar PubMed PubMed Central

29. Bayer, GmbH. Open systems pharmacology suite [Online]; 2023. Available from: https://docs.open-systems-pharmacology.org/working-with-pk-sim/pk-sim-documentation [Accessed 11 Jan 2024].Search in Google Scholar

30. Alsmadi, MM, Al Eitan, LN, Idkaidek, NM, Alzoubi, KH. The development of a PBPK model for atomoxetine using levels in plasma, saliva and brain extracellular fluid in patients with normal and deteriorated kidney function. CNSNDDT 2022;21:704–16. https://doi.org/10.2174/1871527320666210621102437.Search in Google Scholar PubMed

31. Alsmadi, MM, AL-Daoud, NM, Jaradat, MM, Alzughoul, SB, Abu Kwiak, AD, Abu Laila, SS, et al.. Physiologically-based pharmacokinetic model for alectinib, ruxolitinib, and panobinostat in the presence of cancer, renal impairment, and hepatic impairment. Biopharm Drug Dispos 2021;42:263–84. https://doi.org/10.1002/bdd.2282.Search in Google Scholar PubMed

32. Yamamoto, Y, Välitalo, PA, Wong, YC, Huntjens, DR, Proost, JH, Vermeulen, A, et al.. Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach. Eur J Pharmaceut Sci 2018;112:168–79. https://doi.org/10.1016/j.ejps.2017.11.011.Search in Google Scholar PubMed

33. Brodie, M, Muir, S, Agnew, E, MacPhee, G, Volo, G, Teasdale, E, et al.. Protein binding and CSF penetration of phenytoin following acute oral dosing in man. Br J Clin Pharmacol 1985;19:161–8. https://doi.org/10.1111/j.1365-2125.1985.tb02627.x.Search in Google Scholar PubMed PubMed Central

34. Ke, AB, Nallani, SC, Zhao, P, Rostami-Hodjegan, A, Unadkat, JD. Expansion of a PBPK model to predict disposition in pregnant women of drugs cleared via multiple CYP enzymes, including CYP2B6, CYP2C9 and CYP2C19. Br J Clin Pharmacol 2014;77:554–70. https://doi.org/10.1111/bcp.12207.Search in Google Scholar PubMed PubMed Central

35. Abduljalil, K, Furness, P, Johnson, TN, Rostami-Hodjegan, A, Anatomical, SH. Physiological and metabolic changes with gestational age during normal pregnancy. Clin Pharmacokinet 2012;51:365–96. https://doi.org/10.2165/11597440-000000000-00000.Search in Google Scholar PubMed

36. Kilpatrick, C, Wanwimolruk, S, Wing, L. Plasma concentrations of unbound phenytoin in the management of epilepsy. Br J Clin Pharmacol 1984;17:539–46. https://doi.org/10.1111/j.1365-2125.1984.tb02387.x.Search in Google Scholar PubMed PubMed Central

37. Johnson, TN, Rostami-Hodjegan, A, Tucker, GT. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet 2006;45:931–56. https://doi.org/10.2165/00003088-200645090-00005.Search in Google Scholar PubMed

38. Molnár, P, Erdő, SL. Vinpocetine is as potent as phenytoin to block voltage-gated Na+ channels in rat cortical neurons. Eur J Pharmacol 1995;273:303–6. https://doi.org/10.1016/0014-2999(94)00755-V.Search in Google Scholar PubMed

39. Nau, H, Kuhnz, W, Egger, HJ, Rating, D, Helge, H. Anticonvulsants during pregnancy and lactation. Transplacental, maternal and neonatal pharmacokinetics. Clin Pharmacokinet 1982;7:508–43. https://doi.org/10.2165/00003088-198207060-00003.Search in Google Scholar PubMed

40. Paxton, J, Whiting, B, Stephen, K. Phenytoin concentrations in mixed, parotid and submandibular saliva and serum measured by radioimmunoassay. Br J Clin Pharmacol 1977;4:185–91. https://doi.org/10.1111/j.1365-2125.1977.tb00692.x.Search in Google Scholar PubMed PubMed Central

41. Bajpai, M, Roskos, LK, Shen, DD, Levy, RH. Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite. Drug Metab Dispos 1996;24:1401–3.Search in Google Scholar

42. Idkaidek, N, Arafat, T. Saliva versus plasma pharmacokinetics: theory and application of a salivary excretion classification system. Mol Pharm 2012;9:2358–63. https://doi.org/10.1021/mp300250r.Search in Google Scholar PubMed

43. Lander, C, Smith, M, Chalk, J, De Wytt, C, Symoniw, P, Livingstone, I, et al.. Bioavailability and pharmacokinetics of phenytoin during pregnancy. Eur J Clin Pharmacol 1984;27:105–10. https://doi.org/10.1007/BF02395215.Search in Google Scholar

44. Gabrielsson, JL, Johansson, P, Bondesson, U, Karlsson, M, Paalzow, LK. Analysis of pethidine disposition in the pregnant rat by means of a physiological flow model. J Pharmacokinet Biopharm 1986;14:381–95. https://doi.org/10.1007/BF01059198.Search in Google Scholar PubMed

45. Wilder, BJ, Ramsay, RE, Willmore, LJ, Feussner, GF, Perchalski, RJ, Shumate, Jr JB. Efficacy of intravenous phenytoin in the treatment of status epilepticus: kinetics of central nervous system penetration. Ann Neurol 1977;1:511–8. https://doi.org/10.1002/ana.410010602.Search in Google Scholar PubMed

46. Itoh, T, Sawada, Y, Lin, T, Iga, T, Nanano, M. Kinetic analysis of phenytoin disposition in rats with experimental renal and hepatic diseases. J Pharmacobio-Dyn 1988;11:289–308. https://doi.org/10.1248/bpb1978.11.289.Search in Google Scholar PubMed

47. Samrén, EB, Van Duijn, CM, Lieve Christiaens, G, Hofman, A, Lindhout, D. Antiepileptic drug regimens and major congenital abnormalities in the offspring. Ann Neurol 1999;46:739–46.10.1002/1531-8249(199911)46:5<739::AID-ANA9>3.3.CO;2-USearch in Google Scholar

48. Bromfield, EB, Dambrosia, J, Devinsky, O, Nice, FJ, Theodore, WH. Phenytoin withdrawal and seizure frequency. Neurology 1989;39:905–9. https://doi.org/10.1212/wnl.39.7.905.Search in Google Scholar PubMed

49. Kuhnz, W, Koch, S, Helge, H, Nau, H. Primidone and phenobarbital during lactation period in epileptic women: total and free drug serum levels in the nursed infants and their effects on neonatal behavior. Dev Pharmacol Ther 1988;11:147–54. https://doi.org/10.1159/000457682.Search in Google Scholar PubMed

Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/dmpt-2024-0037).

Received: 2024-05-07
Accepted: 2024-06-27
Published Online: 2024-08-08

© 2024 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/dmpt-2024-0037
Keywords for this article
neonatal withdrawal seizures; neuroprotection via inhibition of voltage-gated Na+ channels; PBPK modeling; transplacental diffusion of phenytoin

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. The potential antibacterial effects of tea polyphenols
  4. Original Articles
  5. Bottom-up PBPK modeling of phenytoin brain disposition in postpartum newborns after intrauterine dosing
  6. Molecular pathogenesis of microsatellite instability-high early-stage colorectal adenocarcinoma in India
  7. Effect of a polyherbal Unani formulation on left ventricular diastolic dysfunction in hypertensive patients – a randomized single blind placebo controlled clinical trial
  8. Acute and sub-chronic oral GLP toxicity of Withania somnifera root extract in Sprague Dawley rats
  9. Short Communication
  10. Allelic frequencies of polymorphism c.521T>C (rs4149056) favor preemptive SLCO1B1 genotyping in Armenia
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