POPULATION PHARMACOKINETICS AND PHARMACODYNAMICS OF PEGYLATED-LIPOSOMAL DOXORUBICIN IN PATIENTS WITH AIDS-RELATED KAPOSIS-SARCOMA

Objective: To characterize the population pharmacokinetics of pegylate d-liposomal doxorubicin in patients with acquired immunodeficiency dis ease (AIDS)-related Kaposi's sarcoma and to explore the relationship b etween response of the cutaneous Kaposi's sarcoma lesions to treatment and measures of drug exposure. Methods: Forty-three male patients (me dian age, 40 years; age range, 28 to 50 years), body surface area, 1.8 9 m(2); range, 1.5 to 2.3 m(2)) with AIDS and at least five biopsy-pro ven cutaneous Raposi's sarcoma lesions were randomized to receive eith er a 10 or 20 mg/m(2) dose of study drug for their first cycle and the alternate dose 3 weeks later. Patients continued to receive the study drug at a dose of 20 mg/m(2) every 3 weeks. Serial blood samples were obtained after the first two doses and analyzed by HPLC for determina tion of total plasma doxorubicin concentration. Kaposi's sarcoma lesio n response was categorized as either progressive disease, stable disea se, partial response, or complete response. Classification and regress ion tree (CART) analysis was used to determine the relationship betwee n drug exposure and categorical lesion response. Iterative two-stage a nalysis was used to characterize both the pharmacokinetics of pegylate d-liposomal doxorubicin and to model the probabilities of achieving a specific lesion response. Results: The pharmacokinetics of pegylated-l iposomal doxorubicin were best described by a two-compartment linear s tructural model. Lesion response was significantly related to both the average daily maximum doxorubicin concentration (C-max,C-avg) and dos e intensity. Conclusions: The pharmacokinetics of pegylated-liposomal doxorubicin are strikingly different from conventional doxorubicin. Id entification of both C-max,C-avg and dose intensity as predictors of l esion response will provide guidelines for future dosing regimen desig ns.