Using pharmacokinetics in drug therapy. VI: Comparing methods for dealing with nonlinear drugs like phenytoin

Four methods for estimating dosage regimens for drugs exhibiting non-linear pharmacokinetic behavior (e.g., phenytoin) are described and compared. Estimations of phenytoin Vmax (maximum rate of drug metabolism) and Km (dissociation constant of drug-enzyme complex), and resulting dosage estimates arrived at by four methods were compared with values in six cases. All four methods provided pharmacokinetic estimates that shorten the period of dose titration and improve estimates of phentoin levels. Given a minimum amount of dose-versus-plasma-level data, all four methods provided reliable and comparable estimates of dosage regimens, although one method based on a nomogram sometimes estimated a narrower range of dosage regimens and plasma levels. When there is a potential for inaccuracy in the plasma-level-data, however, the estimated dosage regimens may be too unreliable for practical application.