Acute Phenytoin and Primidone Intoxication A Pharmacokinetic Analysis

Abstract: Serial plasma levels of phenytoin, primidone, and phenobarbital were determined in a patient following a massive overdose of phenytoin and primidone. The patient's neurologic status improved slowly over a period of 10 days and correlated best with the rise and fall of phenytoin plasma concentrations. The pharmacokinetics of all three agents were characterized by nonlinear regression analysis of their respective plasma concentration‐time profiles during the elimination phase, followed by analog computer simulations of their entire plasma concentration‐time course. The computer‐simulated phenytoin plasma concentration‐time profile closely resembled the observed values. Average values of K_m and V_max obtained from patients undergoing chronic therapy were used in the simulation and appear to adequately describe phenytoin elimination in this overdose situation. The elimination half‐lives of primidone and phenobarbital of 6.2 and 83.5 hours, respectively, were within the “normal range” for patients on chronic therapy. Two distinct absorption phases for primidone and three for phenytoin were noted. The marked decrease in the estimated absorption rate constant between phases 1 and 2 for each drug may have been due to slow dissolution of a large congealed mass of phenytoin and primidone in the gut. The analysis of serial plasma samples following a massive overdose is recommended to provide a reliable data base for therapeutic decisions. 1981 American College of Clinical Pharmacology