International Journal of Clinical Pharmacy

, Volume 35, Issue 5, pp 790–797 | Cite as

Intravenous phenytoin: a retrospective analysis of Bayesian forecasting versus conventional dosing in patients

  • Andrea Tobler
  • Stefan MühlebachEmail author
Research Article


Background In the hospital, medication management for effective antiepileptic therapy with phenytoin (PHT) often needs rapid IV loading and subsequent dose adjustment according to therapeutic drug monitoring (TDM). Objective To investigate PHT performance in reaching therapeutic target serum concentration rapidly and sustainably, a Bayesian forecasting (BF) regimen was compared to conventional dosing (CD), according to the official summary of product characteristics. Setting A 500–600 bed acute care teaching hospital in Switzerland, serving as a referral centre for neurology and neurosurgery. Method In a retrospective, single centre, long-term analysis of hospitalized in- and out-patients, all PHT serum tests from the central hospital laboratory from 1997 to 2007 were assessed. The BF regimen consisted of a guided, body weight-adapted rapid IV PHT loading over 5 days with pre-defined TDM time points. The conventional dosage was performed without written guidance. Assuming non-normally distributed data, non-parametric statistical methods for analysis were applied. Main outcome measure The extent of target therapeutic PHT serum levels (40–80 μmol/L) was measured and compared between the two regimens. Also, the influence of gender and age was analysed. Results A total of 6,120 PHT serum levels (2,819 BF and 3,301 conventionally dosed) from 2,589 patients (869 BF and 1,720 conventionally dosed) were evaluated and compared. 63.6 % of the PHT serum levels from the BF group were within the therapeutic range, compared with only 34.0 % in the conventional group (p < 0.0001). The mean BF serum level was 52.0 ± 22.1 μmol/L (within target range) (n = 2,819), whereas the mean serum level of the CD was 39.8 ± 28.2 μmol/L (sub-target range) (n = 3,301). In the BF group, men had small but significantly lower PHT serum levels compared to women (p < 0.0001). The conventionally dosed group showed no significant gender differences (p = 0.187). A comparative sub-analysis of age-related groups (children, adolescents, adults, seniors, and elderly) showed significantly lower target levels (p < 0.0001) for each group in the conventional dosed group, compared to BF. Conclusion Comparing the two cohorts, BF with the well-defined dose regimen showed significantly better performance in reaching therapeutic PHT serum levels rapidly and for longer duration.


Bayesian forecasting Conventional dosing Hospital population Medication management Phenytoin Therapeutic drug monitoring 



The authors would like to thank Prof. H. Landolt, MD, head of Neurosurgery at the Kantonsspital Aarau, Switzerland, for his collaboration and contributions to this study and to Prof. A. Huber, MD, head of the Central Medicinal Laboratory also at the Kantonsspital Aarau, for his support. The authors wish to acknowledge the help of PD W. Berchtold, PhD, emeritus from the University of Applied Sciences, Northwestern Switzerland in statistical evaluation as well as Prof. S. Krähenbühl and Prof. HJ. Huwyler from the Pharmaceutical Department of the University of Basel for critically reviewing this manuscript.


The investigation and the PhD grant was supported by the Kantonsspital Aarau (Switzerland); (Fund for Science and Continuing Education) and by the University of Basel (third-party grant FO119900 for Clinical Pharmacy, project on CNS drug kinetics and patient monitoring).

Conflicts of interest

The submitting author is a scientific director at Vifor Pharma Ltd., Glattbrugg, Switzerland and holds an additional appointment at the Medical Faculty and the Dept. of Pharmaceutical Sciences at the University of Basel, with a professorship in pharmacology and hospital pharmacy. Vifor Pharma Ltd. is not involved in this investigation and has no pharmaceutical products, services or R&D related to the topic. Their focus is on iron deficiency treatment especially with IV iron preparations.


  1. 1.
    Temkin NR, Dikmen SS, Wilensky AJ, Keihm J, Chabal S, Winn HR. A randomized, double-blind study of Phenytoin for the prevention of post-traumatic seizures. N Engl J Med. 1990;323:497–502.PubMedCrossRefGoogle Scholar
  2. 2.
    Temkin NR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials. Epilepsia. 2001;42:515–24.PubMedCrossRefGoogle Scholar
  3. 3.
    Schierhout G, Roberts I. Prophylactic antiepileptic agents after head injury: a systematic review. J Neurol Neurosurg Psychiatry. 1998;64:108–12.PubMedCrossRefGoogle Scholar
  4. 4.
    Haltiner A, Newell DW, Temkin NR, Dikmen SS, Winn HR. Side effects and mortality associated with use of Phenytoin for early posttraumatic seizure prophylaxis. J Neurosurg. 1999;91:588–92.PubMedCrossRefGoogle Scholar
  5. 5.
    Neels HM, Sierens AC, Naelaerts K, Scharpé SL, Hatfield GM, Lambert WE. Therapeutic drug monitoring of old and newer anti-epileptic drugs. Clin Chem Lab Med. 2004;42:1228–55.PubMedCrossRefGoogle Scholar
  6. 6.
    Brodie MR, Muir SE, Agnew E, MacPhee GJ, 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.PubMedCrossRefGoogle Scholar
  7. 7.
    Walker MC, Alavijeh MS, Shorvon SD, Patsalos PN. Microdialysis. Study of the Neuropharmacokinetics of Phenytoin in Rat Hippocampus and Frontal Cortex. Epilepsia. 1996;37:421–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Spruill WJ, Wade WE, Cobb HH, Akbari S. Three Michaelis-Menten pharmacokinetic dosing methods compared with physician dosing of Phenytoin in an outpatient neurology practice. Pharmacotherapy. 2001;21:1407–14.PubMedCrossRefGoogle Scholar
  9. 9.
    Grasela TH, Sheiner LB, Rambeck B, Boenigk HE, Dunlop A, Mullen PW, et al. Steady-state pharmacokinetics of Phenytoin from routinely collected patient data. Clin Pharmacokinet. 1983;8:355–64.PubMedCrossRefGoogle Scholar
  10. 10.
    Evens RP, Fraser DG, Ludden TM, Sutherland EW. Phenytoin toxicity and blood levels after a large oral dose. Am J Hosp Pharm. 1980;37:232–5.PubMedGoogle Scholar
  11. 11.
    Morant J, Ruppaner H. Pfizer Phenhydan®. Arzneimittelkompendium der Schweiz. Basel: Documed AG; 2008. p. 3021–4.Google Scholar
  12. 12.
    Morant J, Ruppaner H. Desitin Epanutin®. Arzneimittel-Kompendium der Schweiz. Basel: Documed AG; 2005. p. 997–1000.Google Scholar
  13. 13.
    Martinelli EF, Mühlebach SF. Rapid i.v. loading with phenytoin with subsequent dose adaptation using non-steady-state serum levels and a Bayesian forecasting computer program to predict maintenance doses. J Clin Pharm Ther. 2003;28:385–93.PubMedCrossRefGoogle Scholar
  14. 14.
    Privitera MD, Homan RW, Ludden TM, Peck CC, Vasko MR. Clinical utility of Bayesian dosing program for phenytoin. Ther Drug Monit. 1989;11(3):285–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Crowley JJ, Koup JR, Cusack BJ, Ludden TM, Vestal RE. Evaluation of a proposed method for phenytoin maintenance dose prediction following an intravenous loading dose. Eur J Clin Pharmacol. 1987;32(2):141–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Yuen GJ, Taylor JW, Ludden TM, Murphy MJ. Predicting phenytoin dosages using Bayesian feedback: a comparison with other methods. Ther Drug Monit. 1983;5(4):437–41.PubMedCrossRefGoogle Scholar
  17. 17.
    Garcia MJ, Gavira R, Santos Buelga D, Dominguez-Gil A. Predictive performance of two phenytoin pharmacokinetic dosing programs from nonsteady state data. Ther Drug Monit. 1994;16(4):380–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Gaulier JM, Boulieu R, Fischer C, Mauguiere F. Evaluation of a bayesian pharmacokinetic program for phenytoin concentration predictions in outpatient population. Eur J Drug Metab Pharmacokinet 1998;23(2):295–300.Google Scholar
  19. 19.
    Zaccara G, Messori A, Muscas GC, Albani F, Baruzzi A, Bianchi A, et al. Predictive performance of pharmacokinetic methods for phenytoin dosing: a multi-center evaluation in 282 patients with epilepsy. Epilepsy Res. 1989;3(3):253–61.PubMedCrossRefGoogle Scholar
  20. 20.
    Godley PJ, Ludden TM, Clementi WA, Godley SE, Ramsey RR. Evaluation of a Bayesian regression-analysis computer program using non-steady-state phenytoin concentrations. Clin Pharm. 1987;6(8):634–9.PubMedGoogle Scholar
  21. 21.
    Martinelli EF. Therapeutisches Monitoring von Phenytoin im Krankenhaus: Untersuchung zur schnellen i.v.-Aufsättigung und Dosisvoraussage mittels Bayesian Forecasting, zur Laborbestimmung und zur Phänotypisierung der Metabolisierungsgeschwindigkeit. Bern: Schweizerische Nationalbibliothek; 1994.Google Scholar
  22. 22.
    Vozeh S, Uematsu T, Aarons L, Maitre P, Landolt H, Gratzl O. Intravenous phenytoin loading in patients after neurosurgery and in status epilepticus. A population pharmacokinetic study. Clin Pharmacokinet. 1988;14:122–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Swadron SP, Rudis MI, Azimian K, Beringer P, Fort D, Orlinsky MA. Comparison of Phenytoin-loading Techniques in the Emergency Department. Acad Emerg Med. 2004;11:244–52.PubMedCrossRefGoogle Scholar
  24. 24.
    Hayes G, Kootsikas ME. Reassessing the lower end of the phenytoin therapeutic range: a review of the literature. Ann Pharmacother. 1993;27:1389–92.PubMedGoogle Scholar
  25. 25.
    Perucca E, Berlowitz D, Birnbaum A, Cloyd JC, Garrard J, Hanlon JT, et al. Pharmacological and clinical aspects of antiepileptic drug use in elderly. Epilepsy Res. 2006;68S:49–63.CrossRefGoogle Scholar
  26. 26.
    Bach B, Hansen JM, Kampmann JP, Rasmussen SN, Skovsted L. Disposition of antipyrine and phenytoin correlated with age and liver volume in man. Clin Pharmacokinet. 1981;6:389–96.PubMedCrossRefGoogle Scholar
  27. 27.
    Estruch J, Galdames D, Martinetti A, Saavedra I. Phenytoin pharmacokinetics in young and older adults. Rev Med Chil. 1992;120:1106–9.PubMedGoogle Scholar
  28. 28.
    Blain PG, Mucklow JC, Bacon CJ, Rawlins MD. Pharmacokinetics of phenytoin in children. Br J Clin Pharmacol. 1981;12(5):659–61.PubMedCrossRefGoogle Scholar
  29. 29.
    Bauer LA, Blouin RA. Age and phenytoin kinetics in adult epileptics. Clin Pharmacol Ther. 1982;31:301–4.PubMedCrossRefGoogle Scholar
  30. 30.
    Battino D, Croci D, Mamoli D, Messina S, Perucca E. Influence of aging on serum phenytoin concentrations: a pharmacokinetic analysis based on therapeutic drug monitoring data. Epilepsy Res. 2004;59:155–65.PubMedCrossRefGoogle Scholar
  31. 31.
    Sketris IS, Langille Ingram EM, Lummis HL. Strategic opportunities for effective optimal prescribing and medication management. Can J Clin Pharmacol. 2009;16:e103–25.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Division of Clinical Pharmacy and Epidemiology and Hospital PharmacyUniversity of BaselBaselSwitzerland

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