International Journal of Clinical Pharmacy

, Volume 38, Issue 2, pp 303–309 | Cite as

Free phenytoin assessment in patients: measured versus calculated blood serum levels

  • Andrea Tobler
  • Raphael Hösli
  • Stefan MühlebachEmail author
  • Andreas Huber
Research Article


Background Total serum drug levels are routinely determined for the therapeutic drug monitoring of selected, difficult-to-dose drugs. For some of these drugs, however, knowledge of the free fraction is necessary to adapt correct dosing. Phenytoin, with its non-linear pharmacokinetics, >90 % albumin binding and slow elimination rate, is such a drug requiring individualization in patients, especially if rapid intravenous loading and subsequent dose adaptation is needed. In a prior long-term investigation, we showed the excellent performance of pharmacy-assisted Bayesian forecasting support for optimal dosing in hospitalized patients treated with phenytoin. In a subgroup analysis, we evaluated the suitability of the Sheiner-Tozer algorithm to calculate the free phenytoin fraction in hypoalbuminemic patients. Objective To test the usefulness of the Sheiner-Tozer algorithm for the correct estimation of the free phenytoin concentrations in hospitalized patients. Setting A Swiss tertiary care hospital. Method Free phenytoin plasma concentration was calculated from total phenytoin concentration in hypoalbuminemic patients and compared with the measured free phenytoin. The patients were separated into a low (35 ≤ albumin ≥ 25 g/L) and a very low group (albumin <25 g/L) for comparing and statistically analyzing the calculated and the measured free phenytoin concentration. Main outcome measures Calculated and the measured free phenytoin concentration. Results The calculated (1.2 mg/L (SD = 0.7) and the measured (1.1 mg/L (SD = 0.5) free phenytoin concentration correlated. The mean difference in the low and the very low albumin group was: 0.10 mg/L (SD = 1.4) (n = 11) and 0.13 mg/L (SD = 0.24) (n = 12), respectively. Although the variability of the data could be a bias, no statistically significant difference between the groups was found: t test (p = 0.78), the Passing–Bablok regression, the Spearman’s rank correlation coefficient of r = 0.907 and p = 0.00. The Bland–Altman plot including the regression analysis revealed no systematic differences between the calculated and the measured value [M = 0.11 (SD = 0.28)]. Conclusion In absence of a free phenytoin plasma concentration measurement also in hypoalbuminemic patients, the Sheiner-Tozer algorithm represents a useful tool to assist therapeutic monitoring to calculate or control free phenytoin by using total phenytoin and the albumin concentration.


Phenytoin Serum concentrations Sheiner-Tozer equation Therapeutic Drug Monitoring (TDM) 



The authors would especially like to thank Erica Holt and Bettina Nyffengger, University of Bern, for their helpful advice and support.


The investigation was supported by the Kantonsspital Aarau (Switzerland); (Fund for Science and Continuing Education) and the University of Basel (third-party Grant FO119900 for Clinical Pharmacy, and related scientific projects).

Conflicts of interest

The authors declare no conflicts of interest. The submitting author is scientific director at Vifor Pharma Ltd. The company has not been involved in this investigation and did not influence any aspect of the study.


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Copyright information

© Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2016

Authors and Affiliations

  • Andrea Tobler
    • 1
  • Raphael Hösli
    • 1
  • Stefan Mühlebach
    • 1
    Email author
  • Andreas Huber
    • 2
  1. 1.Division of Clinical Pharmacy and Epidemiology and Hospital PharmacyUniversity of BaselBaselSwitzerland
  2. 2.Kantonsspital AarauAarauSwitzerland

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