Phenylacetate pharmacokinetics based on iterative two-stage population analysis

Study Objective. To determine the population pharmacokinetics of phenylacetate using iterative two-stage analysis implemented with ADAPT II software. Setting. United States government research hospital. Design. Retrospective pharmacokinetic analysis. Subjects. Sixty-seven patients with refractory solid tumors. Intervention. Subjects received from 1-10 courses/individual (total 141 courses) of therapy with either twice-daily administration or continuous infusions of phenylacetate. Measurements and Main Results. Extensive plasma concentration measurements were performed after the initial dose or start of infusion, with sparse sampling during subsequent courses of therapy. Phenylacetate plasma concentration-time profiles were described by a one-compartment, capacity-limited clearance model with incorporation of parameters to describe extent of induction of clearance and the rate of induction. Median estimates for volume of distribution, maximum rate of drug elimination, Michaelis-Menten constant, and induction factor, and rate of onset of induction of drug clearance were 0.33 (0.26, 0.48) L/kg, 21.8 (16.3, 28.0) mg/kg/hour, 94.6 (48.8, 153.0) mg/L, 1.28 (1.06, 1.66), and 0.0038 (0.0019, 0.0058) hour^-1, respectively. Conclusion. The results of this study are similar to previous pharmacokinetic evaluations using the Abbottbase PKS system but suggest that earlier analyses were suboptimal.