RESEARCH ARTICLE Free phenytoin assessment in patients: measured versus calculated blood serum levels Andrea Tobler 1 • Raphael Ho ¨sli 1 • Stefan Mu ¨ hlebach 1 • Andreas Huber 2 Received: 1 February 2015 / Accepted: 20 December 2015 Ó Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2016 Abstract Background Total serum drug levels are rou- tinely 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 phar- macokinetics, [ 90 % albumin binding and slow elimina- tion rate, is such a drug requiring individualization in patients, especially if rapid intravenous loading and sub- sequent dose adaptation is needed. In a prior long-term investigation, we showed the excellent performance of pharmacy-assisted Bayesian forecasting support for opti- mal 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 hospi- talized patients. Setting A Swiss tertiary care hospital. Method Free phenytoin plasma concentration was calcu- lated from total phenytoin concentration in hypoalbu- minemic patients and compared with the measured free phenytoin. The patients were separated into a low (35 B albumin C 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 correla- tion 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 mea- surement also in hypoalbuminemic patients, the Sheiner- Tozer algorithm represents a useful tool to assist thera- peutic monitoring to calculate or control free phenytoin by using total phenytoin and the albumin concentration. Keywords Phenytoin Á Serum concentrations Á Sheiner- Tozer equation Á Therapeutic Drug Monitoring (TDM) Impact on practice • The Sheiner-Tozer algorithm can be successfully used to calculate a missing free phenytoin plasma concen- tration using the total phenytoin and the albumin plasma levels in hypoalbuminemic patients. • The Sheiner-Tozer algorithm represents a useful and shortly available calculation tool to assist Therapeutic Drug Monitoring and appropriate dose adjustment of a critical dose drug based on the free dose fraction, e.g. & Stefan Mu ¨hlebach stefan.muehlebach@unibas.ch 1 Division of Clinical Pharmacy and Epidemiology and Hospital Pharmacy, University of Basel, Spitalstrasse 26, 4031 Basel, Switzerland 2 Kantonsspital Aarau, Tellstrasse 25, 5001 Aarau, Switzerland 123 Int J Clin Pharm DOI 10.1007/s11096-015-0241-x