Interindividual variation in the extent and rate of phenytoin accumulation

Steady-state serum phenytoin concentration (Css) is known to increase nonlinearly with dose, but it is less well recognized that the rate of phenytoin accumulation is also dose dependent. This stimulation study estimated the extent and rate of phenytoin accumulation in a sample of 95 adult subjects, with known values of Vmax and Km, pooled from the literature. Simulations were done using a Michaelis-Menten model and phenytoin sodium doses of 200, 300, and 400 mg/day. The distributions of Css and the time required to reach 90% of steady state (T90) became increasingly positively skewed as dose was increased. The T90 and Css were positively correlated (r greater than or equal to 0.8880, p less than 0.00001) and subjects reached 90% or more of Css more slowly as the initial phenytoin dose was increased. At an initial dose of 300 mg/day of phenytoin sodium, mean Css was 11.0 +/- 9.10 micrograms/ml (median, 7.62 micrograms/ml), and mean T90 was 12.2 +/- 15.4 days (median, 5.98 days). Only 25.3% of the subjects would be expected to achieve therapeutic serum concentrations (10-20 micrograms/ml) on this dose, and 88.4% would reach 0.9 Css within 30 days. Phenytoin dosage must be individualized to achieve concentrations of 10-20 micrograms/ml. Multiple serum phenytoin determinations during the first 30 days or more are required to determine that steady state has been reached, but these need not be done more often than once a week.