Population pharmacokinetics of phenytoin in adult patients
Abstract Phenytoin (DPH) is an antiepileptic drug used in the first line of focal seizures and tonic-clonic seizures treatments. Phenytoin shows a highly protein binding, non-lineal dose-dependent kinetics, large pharmacokinetic variability and narrow therapeutic index; reasons why this antiepileptic is commonly monitored to optimize the efficacy/toxicity balance. The aim of the present work was to characterize the DPH pharmacokinetics in adult population. Drug plasma levels at steady-state from 215 adult patients were used to develop a population pharmacokinetic model (PopPK) using a non-linear mixed effect modelling approach with NONMEM v.7.3. Pharmacokinetics of DPH were described following one-compartment distribution model with zero-order absorption and Michaelis-Menten non-lineal saturable elimination. Age, weight, magnitude of DPH dose and co-medication with valproic acid have been shown influence on maximum velocity of PHT elimination, significantly decreasing the variability of this pharmacokinetic parameter. This preliminary PopPK developed, has shown an adequate evaluation of the descriptive and predictive performance in adult population within a large dose range (50-800 mg/day). However, its implementation in the clinical setting is required to confirm its suitability.
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Alqahtani S, Alzaidi T, Alotaibi M, Alsultan A. Estimation of phenytoin pharmacokinetic parameters in saudi epileptic patients. Pharmacology. 2019; 104(1-2):60-66. https://doi.org/10.1159/000500314
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Beal SL, Sheiner LB, Boeckmann AJ et al. NONMEM 7.1.0 Users 560 Guides. Ellicott City, MD: Icon Development Solutions; 2009
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Eadie MJ. Therapeutic drug monitoring-antiepileptic drugs. Br J Clin Pharmacol. 2002; 46(3):185-193. https://doi.org/10.1046/j.1365-2125.1998.00769.x
Grasela TH, Sheiner LB, Rambeck B, Boenigk HE, Dunlop A, Mullen PW et al. Steady-state pharmacokinetics of phenytoin from routinely collected patient data. Clin Pharmacokinet. 1983; 8(4):355-364. https://doi.org/10.2165/00003088-198308040-00006
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Hvidberg EF, Dam M. Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet. 1976; 1(3):161-188. https://doi.org/10.2165/00003088-197601030-00001
Martin ES, Crismon ML, Godley PJ. Postinduction Carbamazepine Clearance in an Adult Psychiatric Population. Pharmacotherapy. 1991, 11(4):296-302.
Odani A, Hashimoto Y, Takayanagi K, Otsuki Y, Koue T, Takano M et al. Population pharmacokinetics of phenytoin in Japanese patients with epilepsy: analysis with a dose-dependent clearance model. Biol Pharm Bull. 1996;19(3):444-448. https://doi.org/10.1248/bpb.19.444
R Core Team. R: A language and environment for statistical computing. Viena, Austria: R Foundation for Statistical Computing; 2018.
Richens A. Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet. 1979; 4(3):153-169. https://doi.org/10.2165/00003088-197904030-00001
Vajda FJ, Eadie MJ. The clinical pharmacology of traditional antiepileptic drugs. Epileptic Disord. 2014; 16(4):395-408. https://doi.org/10.1684/epd.2014.0704
Winter ME. Phenytoin. En: Koda-Kimble MA (editor). Basic clinical pharmacokinetics. 3.ª ed. Vancouver: Applied Therapeutics; 1994. pp. 312-348.
Yukawa E, Higuchi S, Aoyama T. Population pharmacokinetics of phenytoin from routine clinical data in Japan: an update. Chem Pharm Bull (Tokyo). 1990; 38(7):1973-1976. https://doi.org/10.1248/cpb.38.1973
Bauer LA, Blouin RA. Age and phenytoin kinetics in adult epileptics. Clin Pharmacol Ther. 1982; 31(3):301-304. https://doi.org/10.1038/clpt.1982.37
Beal SL, Sheiner LB, Boeckmann AJ et al. NONMEM 7.1.0 Users 560 Guides. Ellicott City, MD: Icon Development Solutions; 2009
Dodson WE. Nonlinear kinetics of phenytoin in children. Neurology. 1982; 32(1):42-48. https://doi.org/10.1212/WNL.32.1.42
Eadie MJ. Therapeutic drug monitoring-antiepileptic drugs. Br J Clin Pharmacol. 2002; 46(3):185-193. https://doi.org/10.1046/j.1365-2125.1998.00769.x
Grasela TH, Sheiner LB, Rambeck B, Boenigk HE, Dunlop A, Mullen PW et al. Steady-state pharmacokinetics of phenytoin from routinely collected patient data. Clin Pharmacokinet. 1983; 8(4):355-364. https://doi.org/10.2165/00003088-198308040-00006
Gugler R, Manion CV, Azarnoff DL. Phenytoin: pharmacokinetics and bioavailability. Clin Pharmacol Ther. 1976; 19(2):135-142. https://doi.org/10.1002/cpt1976192135
Hvidberg EF, Dam M. Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet. 1976; 1(3):161-188. https://doi.org/10.2165/00003088-197601030-00001
Martin ES, Crismon ML, Godley PJ. Postinduction Carbamazepine Clearance in an Adult Psychiatric Population. Pharmacotherapy. 1991, 11(4):296-302.
Odani A, Hashimoto Y, Takayanagi K, Otsuki Y, Koue T, Takano M et al. Population pharmacokinetics of phenytoin in Japanese patients with epilepsy: analysis with a dose-dependent clearance model. Biol Pharm Bull. 1996;19(3):444-448. https://doi.org/10.1248/bpb.19.444
R Core Team. R: A language and environment for statistical computing. Viena, Austria: R Foundation for Statistical Computing; 2018.
Richens A. Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet. 1979; 4(3):153-169. https://doi.org/10.2165/00003088-197904030-00001
Vajda FJ, Eadie MJ. The clinical pharmacology of traditional antiepileptic drugs. Epileptic Disord. 2014; 16(4):395-408. https://doi.org/10.1684/epd.2014.0704
Winter ME. Phenytoin. En: Koda-Kimble MA (editor). Basic clinical pharmacokinetics. 3.ª ed. Vancouver: Applied Therapeutics; 1994. pp. 312-348.
Yukawa E, Higuchi S, Aoyama T. Population pharmacokinetics of phenytoin from routine clinical data in Japan: an update. Chem Pharm Bull (Tokyo). 1990; 38(7):1973-1976. https://doi.org/10.1248/cpb.38.1973
Tapia Artiles, C., Pérez-Blanco, J. S., Santos Buelga, D., & García Sánchez, M. J. (2020). Population pharmacokinetics of phenytoin in adult patients. FarmaJournal, 5(2), 15–26. https://doi.org/10.14201/fj2020521526
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