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

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.

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

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.

A quantitative phenytoin GC-MS method and its validation for samples from human ex situ brain microdialysis, blood and saliva using solid-phase extraction.

This study describes the development and validation of a gas chromatography-mass spectrometry (GC-MS) method to identify and quantitate phenytoin in brain microdialysate, saliva and blood from human samples. A solid-phase extraction (SPE) was performed with a nonpolar C8-SCX column. The eluate was evaporated with nitrogen (50°C) and derivatized with trimethylsulfonium hydroxide before GC-MS analysis. As the internal standard, 5-(p-methylphenyl)-5-phenylhydantoin was used. The MS was run in scan mode and the identification was made with three ion fragment masses. All peaks were identified with MassLib. Spiked phenytoin samples showed recovery after SPE of ≥94%. The calibration curve (phenytoin 50 to 1,200 ng/mL, n = 6, at six concentration levels) showed good linearity and correlation (r² > 0.998). The limit of detection was 15 ng/mL; the limit of quantification was 50 ng/mL. Dried extracted samples were stable within a 15% deviation range for ≥4 weeks at room temperature. The method met International Organization for Standardization standards and was able to detect and quantify phenytoin in different biological matrices and patient samples. The GC-MS method with SPE is specific, sensitive, robust and well reproducible, and is therefore an appropriate candidate for the pharmacokinetic assessment of phenytoin concentrations in different human biological samples.