Alvariza S, Ibarra M, Vázquez M, Fagiolino P.
Department of Pharmaceutical Sciences, Faculty of Chemistry Universidad de la República, Uruguay
Objectives: In order to understand the nonlinear pharmacokinetic behavior of phenytoin (PHT), a population pharmacokinetic model of PHT and its main metabolite, p-hydroxy-phenytoin (HPPH), including drug enterohepatic cycling was developed and compared with the classic saturable elimination model.
Methods: Eight healthy volunteers (6 men and 2 women) received orally 600 mg of PHT every 72 hours during a 10-day period (four dosing events at day 1, 4, 7 and 10). An immediate release tablet containing 100 mg of PHT was used (Comitoina, Roemmers Laboratories). In order to prevent loss of bioavailability due to PHT limited solubility in gastrointestinal fluids, each dose of 600 mg was divided in three administrations of 200 mg every 2 hours. Plasma levels of PHT and HPPH were measured at day 1 (12 and 24 hours post-dose) and at day 10 (20 samples obtained between 0 and 96 hours post-administration). Pharmacokinetic analysis was performed using NONMEM® 7.3 [1]. Structural and statistical models were evaluated with goodness of fit plots, Akaike information criterion and visual predictive checks.
Results: The final model included one compartment distribution for both PHT and HPPH, with first-order elimination. Fraction of HPPH produced by PHT elimination was fixed to 1, estimating the apparent volume of distribution (Vd) for both compounds. PHT enterohepatic cycling was included in order to account for observed multiple-peaks in plasma using a previously published model [2]. Increase in PHT and HPPH biotransformation clearance, and PHT secretion into bile (CLG) from day 1 to day 10 was included, in accordance to observations and reported PHT inductive properties [3]. This model showed a superior description of data than the classical PHT saturable elimination. Typical estimated parameters for a bodyweight of 70 kg were: PHT initial CL/F (1.35 L/h), PHT final CL/F (2.21 L/h), PHT Vd (61.8 L), PHT absorption constant rate (0.388 h-1), PHT final CLG/F (0.737 L/h), HPPH final CL/F (101 L/h), HPPH Vd (2450 L), constant rate for PHT enzyme and transporter induction (0.0208 h-1) and PHT reabsorption constant rate (0.156 h-1).
Conclusions: A model including PHT recirculation best-described observed PHT and HPPH data. In other dosage regimens, autoinduction of PHT recirculation could explain the decrease in systemic elimination and therefore its nonlinear accumulation.
References:
[1] Beal, S., Sheiner, L.B., Boeckmann, A., & Bauer, R.J. NONMEM User’s Guides 1989-2009; Icon Development Solutions, Ellicott City, MD, USA, 2009
[2] Ibarra, M., Vazquez, M., Fagiolino, P. Population pharmacokinetic model to analyze nevirapine multiple peaks profile after a single oral dose. JPKPD 2014; 41(4).
[3] Alvariza, S., Fagiolino, P., Vazquez, M., Feria-Romero, I., Orozco-Suarez, S. Chronic administration of phenytoin induces efflux transporters overexpression in rats. Pharmacological Reports 2014; 66.
Reference: PAGE 25 (2016) Abstr 6024 [www.page-meeting.org/?abstract=6024]
Poster: Drug/Disease modeling - CNS