CHROMATOGRAPHIC ANALYSIS AND PHARMACOKINETICS OF LIPOSOME-ENCAPSULATED DOXORUBICIN IN NON-SMALL-CELL LUNG-CANCER PATIENTS

A sensitive and specific quantitative assay for total doxorubicin conc entrations in plasma containing liposome-encapsulated doxorubicin hydr ochloride (TLC D-99) was developed, with solvent extraction and revers ed-phase high-performance liquid chromatography (HPLC). Separation of doxorubicin from its metabolites was accomplished with a 15 cm x 3.9 m m i.d., muBondapak phenyl analytical HPLC column. Optimum chromatograp hic conditions, obtained with a mobile phase gradient from 85 to 50% ( v/v) 16 mM ammonium formate buffer in tetrahydrofuran at a flow rate o f 2 mL/min, gave a detection limit of 0.3 pmol/injection. Eleven-point standard curves with from 0.00595 to 29.8 muM TLC D-99 and 0.1 muM in ternal standard in plasma were analyzed on three separate occasions to formally validate this assay. An overall correlation coefficient of 0 .9985 was found for the logarithmic transformed data. The pharmacokine tic characteristics of doxorubicin were investigated after administrat ion of TLC D-99 to 12 non-small-cell lung cancer patients as an intrav enous infusion at doses of 60 and 75 mg/m2. The data are best describe d by a three-compartment model with alpha, beta, and gamma elimination haff-lives of 0.0721, 2.84, and 25.2 h for the 60-mg/m2 group and 0.1 03, 2.56, and 14.9 h for the 75-mg/m2 patients. A mean plasma clearanc e of 9.89 L/h (range: 1.95 to 23.4 L/h) was found for the 60-mg/m2 pat ients, with that from the 75-mg/m2 group being within these values. Me an area under the plasma concentration versus time curve estimates of 37.1 and 47.9 muM/h were observed for the patients receiving 60 and 75 mg/m2, respectively. The plasma concentration-time course for total d oxorubicin following administration of TLC D-99 suggests that the disp osition of the liposomal formulation is determined more by the pharmac okinetics of the liposome than the encapsulated drug.