Draft version 1 - SQUARE

1 - 1 - Draft version 2012 6 17 - 2 - 2 3 TDM TDM

2 P450 TDM - 3 - I II 1 III IV V VI A TDM B TDM C D TDx (FPIA)

3 TDx 2012 TDM TDM (CAP: College of American Pathologists) - 4 - 1 5 96% 4 5 Karceski S, Morrell MJ, Carpenter D.

4 Treatment of epilepsy in adults: expert opinion, 2005. Epilepsy Behav. 2005; 7: S1-S64. Wheless JW, Clarke DF, Arzimanoglou A, et al. Treatment of pediatric epilepsy: expert opinion. J Child Neurol. 2005; 20: S1-S56. Wheless JW, Clarke DF, Arzimanoglou A, et al. Treatment of pediatric epilepsy: European expert opinion. Epileptic Disord. 2007; 9: 353-412. de Tisi J, Bell GS, Peacock JL, et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet. 2011; 378:1388-1395.

5 - 5 - (PHT) TDM TDM 10 20 g/mL 1 2 g/mL A 10 20 g/mL , 1 2 g/mL (Shorvon et al, 1978) Q4 A 100 % 90 % L/kg CYP2C9 CYP2C19 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH)

6 Michaelis-Menten Vmax Km 5 A - 6 - 6-36 5 7 TDM B Vmax Vmax Km TDM (Perucca, 1980, Wallace & Brodie, 1976) TDM (Sheiner & Tozer, 1978)

7 TDM TDM A TDM (Kawasaki et al, 2000) A - 7 - TDM TDM C CYP2C9 CYP2C19 CYP2C19 CYP2C9*1/*3

8 (Odani et al, 1997 Mamiya et al, 1998) CYP2C9*3 3% TDM PubMed ( ) phenytoin/(serum OR plasma) AND drug monitoring 436 hits ( ) AND ( OR ) AND ( OR ) 26 hits Al Za abi M, Lanner A, Xiaonian X, Donovan T, Charles B. Application of routine monitoring data for determination of the population pharmacokinetics and enteral bioavailability of phenytoin in neonates and infants with seizures. Ther Drug Monit. 2006;28:793 9. ( IV) - 8 - Bachmann KA, Belloto Jr RJ.

9 Differential kinetics of phenytoin in elderly patients. Drugs & Aging. 1999;15:235-50. ( I) Kawasaki C, Nishi R, Uekihara S, Hayano S, Otagiri M. Charcoal hemoperfusion in the treatment of phenytoin overdose. Am J Kidney Dis. 2000;35:323-6. ( V) Mamiya K, Ieiri I, Shimamoto J, et al. The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy ; Studies in stereoselective hydroxylation and population pharmacokinetics. Epilepsia 1998;39:1317-23. ( IV) Odani A, Hashimoto Y, Otsuki Y et al.

10 Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy. Clin Pharmacol Ther. 1997;62:287-92. ( IV) Perucca E. Plasma protein binding of phenytoin in health and disease:relevance to therapeutic drug monitoring. Ther Drug Monit. 1980;2:331-344. ( IV) Sheiner LB, Tozer TN. Clinical pharmacokinetics: The use of plasma concentrations of drugs. In: Melmon KL, Morrelli HF, editors. Clinical Pharmacology: Basic Principles in Therapeutics. New York: MacMillan; 1978.