title: Free phenytoin assessment in patients: measured versus calculated blood serum levels.
abstract: 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.
  
  
  METHODS
  A Swiss tertiary care hospital.
  
  
  METHODS
  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.
  
  
  METHODS
  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)].
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Clinical Pharmacy and Epidemiology and Hospital Pharmacy, University of Basel, Spitalstrasse 26, 4031, Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tobler
authors.affiliation: Division of Clinical Pharmacy and Epidemiology and Hospital Pharmacy, University of Basel, Spitalstrasse 26, 4031, Basel, Switzerland.
authors.forename: Raphael
authors.initials: R
authors.lastname: Hösli
authors.affiliation: Division of Clinical Pharmacy and Epidemiology and Hospital Pharmacy, University of Basel, Spitalstrasse 26, 4031, Basel, Switzerland. stefan.muehlebach@unibas.ch.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mühlebach
authors.affiliation: Kantonsspital Aarau, Tellstrasse 25, 5001, Aarau, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Huber
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000927:Anticonvulsants / Q000097:blood*; D002648:Child; D015331:Cohort Studies; D016903:Drug Monitoring / Q000379:methods* / Q000592:standards; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010672:Phenytoin / Q000097:blood*; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D010672:Phenytoin
keywords: Phenytoin; Serum concentrations; Sheiner-Tozer equation; Therapeutic Drug Monitoring (TDM)