Indian Journal of Critical Care Medicine

Register      Login

SEARCH WITHIN CONTENT

FIND ARTICLE

Volume / Issue

Online First

Archive
Related articles

VOLUME 26 , ISSUE 6 ( June, 2022 ) > List of Articles

Original Article

Estimation of Free Phenytoin Concentration in Critically Ill Patients with Hypoalbuminemia: Direct-measurement vs Traditional Equations

Premila M Wilfred, Sumith Mathew, Binila Chacko, Ratna Prabha, Binu Susan Mathew

Keywords : Critical care, Free phenytoin, Hypoalbuminemia, Sheiner–Tozer equation

Citation Information : Wilfred PM, Mathew S, Chacko B, Prabha R, Mathew BS. Estimation of Free Phenytoin Concentration in Critically Ill Patients with Hypoalbuminemia: Direct-measurement vs Traditional Equations. Indian J Crit Care Med 2022; 26 (6):682-687.

DOI: 10.5005/jp-journals-10071-24235

License: CC BY-NC 4.0

Published Online: 20-06-2022

Copyright Statement:  Copyright © 2022; The Author(s).


Abstract

Background: In critically ill patients with low albumin, dose individualization of phenytoin is a challenge. The currently used Sheiner–Tozer equation does not accurately predict the free phenytoin concentration in serum and can result in incorrect dose modifications. The best measure to advocate in these patients is the direct-measurement of free phenytoin concentration. Aims and objectives: Phenytoin exhibits complex pharmacokinetics, requiring careful therapeutic drug monitoring. This study aimed to compare the accuracy of the established Sheiner–Tozer calculation method against the direct-measurement of free phenytoin concentration in serum by high performance liquid chromatography in critically ill patients with low albumin. Materials and methods: Blood specimens for direct-measurement of both total and free phenytoin concentration were obtained from 57 patients with hypoalbuminemia monitored in the intensive care unit. Results: The median [inter-quartile range (IQR)] for Sheiner–Tozer equation calculated total phenytoin concentration and direct-measured total was 17.14 (10.63–24.53) and 9.82 (6.02–13.85) μg mL−1, respectively. Approximately 53 and 5% of patients were found to be subtherapeutic and supratherapeutic for direct-measured total phenytoin concentrations, respectively. In contrast, on applying the Sheiner–Tozer calculation, 23 and 40% had subtherapeutic and supratherapeutic concentrations, respectively, for total phenytoin concentration. The median (IQR) for direct-measured, routine and Sheiner–Tozer equation calculated free phenytoin concentration were 1.92 (1.06–2.76), 0.98 (0.60–1.39), and 1.71 (1.06–2.45) μg mL−1, respectively. Only 45.7% of patients were in agreement with respect to the therapeutic category when direct-measured free was compared against routine calculation free. Conclusion: In patients with low albumin, free phenytoin concentration based on the Sheiner–Tozer corrected equation accurately classified patients based on their therapeutic category of free phenytoin in 73.7% of patients. Hence, for individualization of phenytoin dosage in critically ill patients with low albumin, we recommend direct-measurement of free phenytoin concentration.


PDF Share
  1. World Health Orgainzation. Global epilepsy report 2019.WHO. Available from: https://www.who.int/mental_health/neurology/epilepsy/report_2019/en/
  2. Zafar SN, Khan AA, Ghauri AA, Shamim MS. Phenytoin versus leviteracetam for seizure prophylaxis after brain injury–a meta-analysis. BMC Neurol 2012;12(1):30. DOI: 10.1186/1471-2377-12-30.
  3. Masapu D, Gopala Krishna KN, Sanjib S, Chakrabarti D, Mundlamuri RC, Manohar N, et al. A comparative study of midazolam and target-controlled propofol infusion in the treatment of refractory status epilepticus. Indian J Crit Care Med 2018;22(6):441–448. DOI: 10.4103/ijccm.IJCCM_327_17.
  4. Giancarlo GM, Venkatakrishnan K, Granda BW, von Moltke LL, Greenblatt DJ. Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine. Eur J Clin Pharmacol 2001;57(1):31–36. DOI: 10.1007/s002280100268.
  5. Thakkar AN, Bendkhale SR, Taur SR, Gogtay NJ, Thatte UM. Association of CYP2C9 polymorphisms with phenytoin toxicity in Indian patients. Neurol India 2012;60(6):577−580. DOI: 10.4103/0028-3886.105189.
  6. Anderson GD. Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs. Neurology 2004;63(10 Suppl. 4): S3–S8. DOI: 10.1212/wnl.63.10_suppl_4.s3.
  7. Iwamoto T, Kagawa Y, Naito Y, Kuzuhara S, Okuda M. Clinical evaluation of plasma free phenytoin measurement and factors influencing its protein binding. Biopharm Drug Dispos 2006;27(2): 77–84. DOI: 10.1002/bdd.486.
  8. Jain S, Gautam V, Naseem S. Acute-phase proteins: as diagnostic tool. J Pharm Bioallied Sci 2011;3(1):118–127. DOI: 10.4103/0975-7406.76489.
  9. Levine M, Chang T. Therapeutic drug monitoring of phenytoin. Rationale and current status. Clin Pharmacokinet 1990;19(5):341–358. DOI: 10.2165/00003088-199019050-00001.
  10. Patsalos PN, Berry DJ, Bourgeois BFD, Cloyd JC, Glauser TA, Johannessen SI, 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(7):1239–1276. DOI: 10.1111/j.1528-1167.2008.01561.x.
  11. Nicholson JP, Wolmarans MR, Park GR. The role of albumin in critical illness. Br J Anaesth 2000;85(4):599–610. DOI: 10.1093/bja/85.4.599.
  12. von Winckelmann SL, Spriet I, Willems L. Therapeutic drug monitoring of phenytoin in critically ill patients. Pharmacotherapy 2008;28(11):1391–400. DOI: 10.1592/phco.28.11.1391.
  13. Montgomery MC, Chou JW, McPharlin TO, Baird GS, Anderson GD. Predicting unbound phenytoin concentrations: effects of albumin concentration and kidney dysfunction. Pharmacother J Hum Pharmacol Drug Ther 2019;39(7):756–766. DOI: 10.1002/phar.2273.
  14. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017;43(3):304–377. DOI: 10.1007/s00134-017-4683-6.
  15. Doucet J, Fresel J, Hue G, Moore N. Protein binding of digitoxin, valproate and phenytoin in sera from diabetics. Eur J Clin Pharmacol 1993;45(6):577–579. DOI: 10.1007/BF00315318.
  16. Pillai LV, Vaidya N, Khade AD, Hussainy S. Variability of serum phenytoin levels in critically ill head injured patients in intensive care unit. Indian J Crit Care Med 2008;12(1):24–27. DOI: 10.4103/0972-5229.40946.
  17. Dasgupta A. Usefulness of monitoring free (unbound) concentrations of therapeutic drugs in patient management. Clin Chim Acta 2007;377(1–2):1–13. DOI: 10.1016/j.cca.2006.08.026.
  18. Peterson GM, McLean S, Aldous S, Witt RV, Millingen KS. Plasma protein binding of phenytoin in 100 epileptic patients. Br J Clin Pharmacol 1982;14(2):298–300. DOI: 10.1111/j.1365-2125.1982.tb01981.x.
  19. Interpatient and intrapatient variability in phenytoin protein binding. Abstract. Europe PMC. Available from: https://europepmc.org/article/med/12021629.
  20. Tobler A, Hösli R, Mühlebach S, Huber A. Free phenytoin assessment in patients: measured versus calculated blood serum levels. Int J Clin Pharm 2016;38(2):303–309. DOI: 10.1007/s11096-015-0241-x.
  21. Chesher D. Calculated free phenytoin and albumin adjusted total phenytoin versus measured free phenytoin. Pathology 2019;51:S108. https://doi.org/10.1016/j.pathol.2018.12.303.
  22. Kiang TKL, Ensom MHH. A comprehensive review on the predictive performance of the Sheiner−Tozer and derivative equations for the correction of phenytoin concentrations. Ann Pharmacother 2016;50(4):311–325. DOI: 10.1177/1060028016628166.
  23. Barra ME, Phillips KM, Chung DY, Rosenthal ES. A novel correction equation avoids high-magnitude errors in interpreting therapeutic drug monitoring of phenytoin among critically ill patients. Ther Drug Monit 2020;42(4):617−625. DOI: 10.1097/FTD.0000000000000739.x.
  24. Svensson CK, Woodruff MN, Baxter JG, Lalka D. Free drug concentration monitoring in clinical practice. Rationale and current status. Clin Pharmacokinet 1986;11(6):450–469. DOI: 10.2165/00003088-198611060-00003.
  25. Tacker D, Robinson R, Perrotta PL. Abbott ARCHITECT iPhenytoin assay versus similar assays for measuring free phenytoin concentrations. Lab Med 2014;45(2):176–181. DOI: 10.1309/lm28b9dsrjcbcwwj.
  26. Kilpatrick CJ, Wanwimolruk S, Wing LM. Plasma concentrations of unbound phenytoin in the management of epilepsy. Br J Clin Pharmacol 1984;17(5):539–546. DOI: 10.1111/j.1365-2125.1984.tb02387.x.
  27. Imam SH, Landry K, Kaul V, Gambhir H, John D, Kloss B. Free phenytoin toxicity. Am J Emerg Med 2014;32(10):1301.e3−4. DOI: 10.1016/j.ajem.2014.03.036.
  28. Muñoz–Pichuante D, Villa Zapata L, Cabrera S, Lagos X, Grandjean J. Dosage of phenytoin in neurocritical patients using Bayesian algorithms: a pilot study. Drug Metab Pers Ther 2019;18:34(4):/j/dmdi.ahead-of-print/dmpt-2019-0015/dmpt-2019-0015.xml. DOI: 10.1515/dmpt-2019-0015.
  29. Javadi S-S, Mahjub R, Taher A, Mohammadi Y, Mehrpooya M. Correlation between measured and calculated free phenytoin serum concentration in neurointensive care patients with hypoalbuminemia. Clin Pharmacol Adv Appl 2018;10:183–190. DOI: 10.2147/CPAA.S186322. eCollection 2018.
  30. Hong J-M, Choi Y-C, Kim W-J. Differences between the measured and calculated free serum phenytoin concentrations in epileptic patients. Yonsei Med J 2009;50(4):517–520. DOI: 10.3349/ymj.2009.50.4.517.
  31. Parikh L, MacLaren R. The predictive performances of equations used to estimate unbound phenytoin concentrations in a medical ICU population and the impact of exogenous albumin administration. J Crit Care 2018;44:95–100. DOI: 10.1016/j.jcrc.2017.10.028.
  32. Buckley MS, Reeves BA, Barletta JF, Bikin DS. Correlation of free and total phenytoin serum concentrations in critically pll patients. Ann Pharmacother 2016;50(4):276–281. DOI: 10.1177/1060028015627468.
  33. Krasowski MD, Penrod LE. Clinical decision support of therapeutic drug monitoring of phenytoin: measured versus adjusted phenytoin plasma concentrations. BMC Med Inform Decis Mak 2012;12:7. DOI: 10.1186/1472-6947-12-7.
  34. Soriano VV, Tesoro EP, Kane SP. Characterization of free phenytoin concentrations in end-stage renal disease using the Winter–Tozer equation. Ann Pharmacother 2017;51(8):669–764. DOI: 10.1177/1060028017707541.
  35. McMillin GA, Juenke J, Dasgupta A. Effect of ultrafiltrate volume on determination of free phenytoin concentration. Ther Drug Monit 2005;27(5):630–633. DOI: 10.1097/01.ftd.0000173373.12569.c7.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.