Simultaneous investigation of indinavir nonlinear pharmacokinetics and bioavailability in healthy volunteers using stable isotope labeling technique:Study design and model-independent data analysis

Indinavir follows nonlinear pharmacokinetics upon oral administration at cl inical doses. A study employing the stable isotope administration technique in a three-treatment design was conducted to identify the source of the no nlinearity and to determine the dose-dependency of systemic bioavailability . In treatment A, 400 mg of unlabeled indinavir (D-0) was coadministered or ally with 16 mg of a hexadeutero analogue of indinavir (D-6) intravenously. In treatment B, 800 mg of D-0 po was coadministered with 16 mg of D-6 intr avenously. In treatment C, 16 mg of iv D-6 was infused concurrently with 16 mg iv of D-0. Plasma concentrations of D-0 and D-6 were determined by an L G/MS/MS assay method. Concentrations of indinavir in plasma increased great er than dose-proportionally over the 400- to 800-mg dose range. No meaningf ul kinetic isotope effects were found in treatment C. Plasma concentrations of D-6 were dependent on the coadministered D-0-indinavir dose and were lo west in treatment C, higher in treatment A, and highest in treatment B. The bioavailability of indinavir was high (60-65%) and comparable between the 400- and 800-mg doses. There was a significant contribution of nonlinear ki netics in the systemic circulation to the observed disproportional increase in plasma concentrations following oral dosing, The high bioavailability a t clinically relevant doses suggests a high degree of saturation of first-p ass metabolism. These results further demonstrate that the concomitant admi nistration technique in combination with the LC/MS/MS method can provide a realistic and reliable means of elucidating important pharmacokinetic prope rties of drug candidates during product development.