Bioavailability Studies of Drugs with Nonlinear Pharmacokinetics: II. Absolute Bioavailability of Intravenous Phenytoin Prodrug at Therapeutic Phenytoin Serum Concentrations Determined by Double‐Stable Isotope Technique

Measurement of the absolute bioavailability of phenytoin (PHT) derived from test doses of Phenytoin prodrug (PPD) at therapeutic PHT serum concentrations is complicated by two problems: 1) the area under the serum concentration versus time curve (AUC) produced by a given size of test dose will vary directly with background PHT serum concentration due to the nonlinear pharmacokinetic properties of PHT; 2) PPD is more water soluble than PHT, making renal excretion of PPD more likely. The authors describe a double-stable isotope method that obviates these two problems. Using only six subjects, the authors were able to demonstrate bioequivalence of PHT derived from intravenous PPD with intravenous PHT by current FDA standards for AUC ratio of test/reference formulation (90% confidence intervals between 0.80 and 1.20; ratio ⋝ 0.80 in ⋝ 80% of subjects; statistical power to detect a difference of 0.20 with a probability of 0.80).