Free phenytoin assessment in patients: measured versus calculated blood serum levels
Tóm tắt
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.
Tài liệu tham khảo
Bullock MR, Povlishock JT. Guidelines for the management of severe traumatic brain injury. Editor’s Commentary. J Neurotrauma. 2007;24 Suppl 1:2 p (preceding S1. Erratum in: J Neurotrauma. 2008;25(3):276–8).
Evans WE, Oellerich M, Holt DW. Drug monitoring, Leitfaden für die klinische Praxis. 2nd ed. Wiesbaden: Abbott; 1994.
Micromedex [Internet]. Greenwood Village: Thomson Reuters, (cited 2011 Oct 5). http://www.thomsonhc.com/hcs/librarian/ND_T/HCS/ND_PR/Main/CS/C686E6/DUPLICATIONSHIELDSYNC/89B08F/ND_PG/PRIH/ND_B/HCS/SBK/2/ND_P/Main/PFActionId/hcs.common.RetrieveDocumentCommon/DocId/105/ContentSetId/68/SearchTerm/phenytoin/SearchOption/BeginWith.
Adam D, Büch HP, Büch U, Christ W, Coper H, Dörfler H, et al. Allgemeine und Spezielle Pharmakologie und Toxikologie. 5th ed. Mannheim: Wissenschaftsverlag; 1987.
Schaefer U, Höchner P, Karrer C. Arzneimittel-Kompendium der Schweiz. 32nd ed. Basel: Documed AG; 2011.
Martin E, Tozer TN, Sheiner LB, Riegelman S. The clinical pharmacokinetics of phenytoin. J Pharmacokinet Biopharm. 1977;5(6):579–96.
Queckenberg C, Fuhr U. Influence of posture on pharmacokinetics. Eur J Clin Pharmacol. 2009;65(2):109–19.
Dasgupta A. Clinical utility of free drug monitoring. Clin Chem Lab Med. 2002;40(10):986–93.
Soldin SJ. Free drug measurements. When and why? An overview. Arch Pathol Lab Med. 1999;123(9):822–3.
Kumps AH. Therapeutic drug monitoring: a comprehensive and critical review of analytical methods for anticonvulsive drugs. J Neurol. 1982;228(1):1–16.
Joerger M, Huitema AD, Boogerd W, van der Sande JJ, Schellens JH, Beijnen JH. Interactions of serum albumin, valproic acid and carbamazepine with the pharmacokinetics of phenytoin in cancer patients. Basic Clin Pharmacol Toxicol. 2006;99(2):133–40.
Zielmann S, Mielck F, Kahl R, Kazmaier S, Sydow M, Kolk J, et al. A rational basis for the measurement of free phenytoin concentration in critically ill trauma patients. Ther Drug Monit. 1994;16(2):139–44.
Johansen K, Krogh M, Andresen AT, Christophersen AS, Lehne G, Rasmussen KE. Automated analysis of free and total concentrations of three antiepileptic drugs in plasma with on-line dialysis and high-performance liquid chromatography. J Chromatogr B Biomed Appl. 1995;669(2):281–8.
Dasgupta A, Timmerman TG. In vitro displacement of phenytoin from protein binding by nonsteroidal antiinflammatory drugs tolmetin, ibuprofen, and naproxen in normal and uremic sera. Ther Drug Monit. 1996;18(1):97–9.
Tobler A, Mühlebach S. Intravenous phenytoin: a retrospective analysis of Bayesian forecasting versus conventional dosing in patients. Int J Clin Pharm. 2013;35(5):790–7.
Siemens Healthcare Diagnostics Inc [Internet]. Syva® EMIT® TDM und Syva® EMIT® Serum Tox® Tests (updated 2010; cited 2015 June 1). http://www.healthcare.siemens.de/siemens_hwem-hwem_ssxa_websites-context-root/wcm/idc/groups/public/@de/@lab/documents/download/mday/mjux/~edisp/dx-de-0700982-syvaemittdmtestsuserumtoxikologie-flyer-01183895.pdf.
Sheiner LB, Tozer TN. Clinical pharmacokinetics: the use of plasma concentrations of drugs. In: Melmon KL, Morelli HF, editors. Clinical pharmacology: basic principles in therapeutics. New York: Macmillan; 1978. p. 71–109.
Passing H, Bablok W. A new biometrical procedure for testing the equality of measurements from two different analytical methods. J Clin Chem Clin Biochem. 1983;21(11):709–20.
Dager WE, Inciardi JF, Howe TL. Estimating phenytoin concentrations by the Sheiner-Tozer method in adults with pronounced hypoalbuminemia. Ann Pharmacother. 1995;29(7–8):667–70.
Hong JM, Choi YC, Kim WJ. Differences between the measured and calculated free serum phenytoin concentrations in epileptic patients. Yonsei Med J. 2009;50(4):517–20.
Wolf GK, McClain CD, Zurakowski D, Dodson B, McManus ML. Total phenytoin concentrations do not accurately predict free phenytoin concentrations in critically ill children. Pediatr Crit Care Med. 2006;7(5):434–9.
Krasowski MD, Penrod LE. Clinical decision support of therapeutic drug monitoring of phenytoin: measured versus adjusted phenytoin plasma concentrations. BMC Med Inform Decis Mak. 2012;14(12):7.
von Winckelmann SL, Spriet I, Willems L. Therapeutic drug monitoring of phenytoin in critically ill patients. Pharmacotherapy. 2008;28(11):1391–400.