Correlation of Free and Total Phenytoin Serum Concentrations in Critically Ill Patients

Buckley, Mitchell S.; Reeves, Brittany A.; Barletta, Jeffrey F.; Bikin, Dale S.

doi:10.1177/1060028015627468

Cited by 16 publications

(19 citation statements)

References 11 publications

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“…Although the median for the unbound plasma fraction of phenytoin in our population is close to previously reported value 16 , the correlation coefficient between the free and total serum PHT levels is low. This weak correlation may be explained in part by hypoalbuminemia as well as use of other medications with high protein bounding capacity 17 or effect on PHT pharmacokinetics through either induction or inhibition of the hepatic cytochrome P450 enzymes involved in PHT metabolism. While the Sheiner-Tozer equation 18 is used to calculate tPHT levels in hypoalbunimic patients, precise adjustments for other factors are not available.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of phenytoin serum levels following a loading dose in the acute hospital setting

Selioutski

Grzesik

Vasilyeva

et al. 2017

Seizure

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Purpose Due to the complex pharmacokinetic profiles of phenytoin (PHT) and fosphenytoin (FOS), achieving sustained, targeted serum PHT levels in the first day of use is challenging. Methods A population based approach was used to analyze total serum PHT (tPHT) level within 2–24 hours of PHT/FOS loading with or without supplementary maintenance or additional loading doses among PHT-naïve patients in the acute hospital setting. Adequate tPHT serum level was defined as ≥ 20 μg/mL. Results Among 494 patients with 545 tPHT serum levels obtained in the first 2–24 hours after the loading dose (LD), tPHT serum levels of either < or ≥ 20 μg/mL were observed along wide and overlapping cumulative dose ranges. Among those receiving 15–20 mg/kg and 20–55 mg/kg weight-based loading dose, 63 % and 51 % respectively did not attain tPHT serum level of ≥ 20 μg/mL even within the first 6 hours of treatment. For the 393 available concomitant free and total serum PHT levels, correlation was weak, r=0.36. Conclusion Close laboratory surveillance and PHT/FOS dose adjustments are recommended to ensure adequate and sustained tPHT serum levels early in treatment. Free serum PHT level is the preferred method of drug monitoring.

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Section: Discussionmentioning

confidence: 99%

Evaluation of phenytoin serum levels following a loading dose in the acute hospital setting

Selioutski

Grzesik

Vasilyeva

et al. 2017

Seizure

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show abstract

“…Patients were excluded if there were presence of hepatic or renal failure, consumption of concomitant medications interfering with phenytoin protein binding or metabolism, such as valproic acid, phenobarbital, heparin, or sulfonamides, and transfusion of blood products and albumin during the study period. Serum albumin levels were categorized into three groups according to the study by Buckley et al: mild hypoalbuminemia (3–3.5 g/dL), moderate hypoalbuminemia (2.5–3 g/dL), and severe hypoalbuminemia (<2.5 g/dL) 13. Relevant demographic and clinical characteristics, including age, sex, body-mass index, ICU-admission indication, serum albumin level, creatinine concentration, total bilirubin concentration, and Glasgow Coma Scale on admission, were recorded for all patients.…”

Section: Methodsmentioning

confidence: 99%

“…In critically ill patients, multiple factors that lead to hypoalbuminemia, such as advanced age, severe infection, inflammation, malnutrition, uremia, and liver failure can alter free phenytoin concentration 13. Therefore, intensive-care unit (ICU) patients are at higher risk of toxic or subtherapeutic serum concentration, which justifies the significance of free phenytoin-concentration monitoring in such patients 14.…”

Section: Introductionmentioning

confidence: 99%

Correlation between measured and calculated free phenytoin serum concentration in neurointensive care patients with hypoalbuminemia

Javadi¹,

Mahjub²,

Taher³

et al. 2018

CPAA

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PurposeIn critically ill patients, monitoring free phenytoin concentration is a valuable method for phenytoin-dosage adjustment. However, due to technical difficulties and the high cost of these methods, the Sheiner–Tozer equation is routinely used for estimating free phenytoin concentration in clinical practice. There have been conflicting results concerning accuracy and precision of the Sheiner–Tozer equation for prediction of free phenytoin concentration in various patient populations. Therefore, this study was conducted to evaluate the accuracy and correlation of measured and calculated free phenytoin concentrations in neurointensive care patients with hypoalbuminemia.MethodsA total of 65 adult neurointensive care patients with hypoalbuminemia who were receiving phenytoin for prevention or treatment of seizures were recruited in this study. In addition to measuring free phenytoin concentration by HPLC, free phenytoin concentration was calculated using both conventional and revised Sheiner–Tozer equations. Eventually, the correlation and level of agreement between measured and calculated free phenytoin concentrations were evaluated.ResultsThe mean albumin concentration of studied patients was 2.63±0.57 g/dL. There was a significant but weak–moderate correlation between measured and calculated free phenytoin concentration using conventional and revised Sheiner–Tozer equations (r=0.45 and r=0.43, respectively). Conventional and revised Sheiner–Tozer equations were not able to predict free phenytoin concentrations accurately in 33.85% and 35.4% of patients, respectively. Although the sex of patients did not have a significant impact on the level of agreement, younger patients had a higher level of agreement.ConclusionAlthough there was a moderate correlation between calculated and measured free phenytoin concentration, the Sheiner–Tozer equation was not able to predict free phenytoin concentration accurately in all patients, especially in older patients. Therefore, monitoring free phenytoin serum concentration besides clinical outcomes should be considered for phenytoin-dose adjustment in critically ill patients.

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“…We would like to thank Kane 1 for his interest in our article 2 and thoughtful comments. He inquired about our laboratory practice of analyzing phenytoin serum concentrations because phenytoin protein binding capacity may be influenced at temperatures greater than room air, which may necessitate modifying our calculations.…”

Section: Letter To the Editormentioning

confidence: 99%

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Buckley¹,

Kaufman²,

Barletta³

et al. 2016

Ann Pharmacother

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We would like to thank Kane 1 for his interest in our article 2 and thoughtful comments. He inquired about our laboratory practice of analyzing phenytoin serum concentrations because phenytoin protein binding capacity may be influenced at temperatures greater than room air, which may necessitate modifying our calculations. Similar to most laboratory practices in US hospitals in analyzing phenytoin serum concentrations, our hospital conducts these processes at room temperature.They also mentioned about the interest of application of our findings to other equations, particularly the traditional and revised Winter-Tozer. We chose to use the traditional Sheiner-Tozer formula because we felt that this is what is typically used in practice and what is taught in training. Interestingly, when we utilized an alternative correction factor (0.29) in our cohort, the correlation did not change (r = 0.817), and agreement with level interpretation was 66% (unpublished data).We agree with the limitations described with the categorizations that were used for level assessment. We choose this method rather than percentage error because as the model for providing clinical pharmacy services is changing, many institutions rely on trigger tools to identify areas for pharmacokinetic interventions. We felt that this method would best reveal the limitations with such a practice as it relates to adjusted phenytoin levels.We both agree that total phenytoin levels cannot be highly reliable in estimating free concentrations in critically ill patients. Furthermore, we recognize that free phenytoin levels may not be readily available at some institutions, which may pose a significant barrier to obtaining real-time data to make clinical decisions. However, increased awareness regarding the limitations with these adjustment equations is needed, as is further research, to identify an accurate surrogate for free phenytoin levels. In all cases, prudent evaluation of clinical response for efficacy and safety is required.

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Correlation of Free and Total Phenytoin Serum Concentrations in Critically Ill Patients

Cited by 16 publications

References 11 publications

Evaluation of phenytoin serum levels following a loading dose in the acute hospital setting

Evaluation of phenytoin serum levels following a loading dose in the acute hospital setting

Correlation between measured and calculated free phenytoin serum concentration in neurointensive care patients with hypoalbuminemia

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