Farmacocinética poblacional de fenitoína en pacientes adultos

  1. Tapia Artiles, Carlos 1
  2. Pérez-Blanco, J. Samuel 1
  3. Santos Buelga, Dolores 1
  4. García Sánchez, María José 1
  1. 1 Universidad de Salamanca
    info

    Universidad de Salamanca

    Salamanca, España

    ROR https://ror.org/02f40zc51

Journal:
Farmajournal

ISSN: 2445-1355

Year of publication: 2020

Volume: 5

Issue: 2

Pages: 15-26

Type: Article

DOI: 10.14201/FJ2020521526 DIALNET GOOGLE SCHOLAR lock_openOpen access editor

More publications in: Farmajournal

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.

Bibliographic References

  • Alqahtani S, Alzaidi T, Alotaibi M, Alsultan A. Estimation of phenytoin pharmacokinetic parameters in saudi epileptic patients. Pharmacology. 2019; 104(1-2):60-66.
  • Bauer LA, Blouin RA. Age and phenytoin kinetics in adult epileptics. Clin Pharmacol Ther. 1982; 31(3):301-304.
  • 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.
  • Eadie MJ. Therapeutic drug monitoring-antiepileptic drugs. Br J Clin Pharmacol. 2002; 46(3):185-193.
  • 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.
  • Gugler R, Manion CV, Azarnoff DL. Phenytoin: pharmacokinetics and bioavailability. Clin Pharmacol Ther. 1976; 19(2):135-142.
  • Hvidberg EF, Dam M. Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet. 1976; 1(3):161-188.
  • 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.
  • 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.
  • Vajda FJ, Eadie MJ. The clinical pharmacology of traditional antiepileptic drugs. Epileptic Disord. 2014; 16(4):395-408.
  • 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.
Data source: Dialnet