Clinical pharmacokinetics and pharmacodynamics of anticancer agents delivered via PEGylated liposomes

PEGylated liposome is one of the most useful nanocarriers for cancer therapy. Studies described in this dissertation provide new knowledge about (1) the nature of nonlinear PK of PEGylated liposomal anticancer agents, (2) the role of the bi-directional interaction between PEGylated liposomes and the monocytes/macrophages in the PK/PD of these agents, and (3) patient factors that significantly influence the PK/PD of PEGylated liposomal anticancer agents.;The PK disposition of encapsulated CPT-11, released CPT-11, and SN-38 after IHL-305 (PEGylated liposomal CPT-11) in cancer patients was evaluated using noncompartmental, individual-based compartmental and population PK analysis. The PK of IHL-305 was characterized by a prolonged circulation time, a reduced volume of distribution and saturable clearance. The high inter-patient variability in the PK and PD of IHL-305 was associated with age, body composition, gender, and monocyte function.;The PK disposition of S-CKD602 (PEGylated liposomal CKD-602) was evaluated using population PK analysis. PK of encapsulated CKD-602 was described by 1-compartment model with nonlinear clearance and PK of released CKD-602 was described by a 2-compartment model with linear clearance for all patients. The release rate of CKD-602 from S-CKD602 was influenced by age and clearance of encapsulated CKD-602 was influenced by presence of tumors in liver.;A mechanism-based PK-PD model was also developed that described the relationship between PEGylated liposomal anticancer drug and monocyte in cancer patients treated with S-CKD602 and IHL-305. In this model, an irreversible uptake of liposomal drug to monocyte was used account for the bi-directional interaction between PEGylated liposomal anticancer drug and monocyte. The degradation of liposomes through routes other than uptake by monocytes was included. The estimated half-life and baseline value of monocytes were close to the published data. The mechanism-based PK-PD model was compared with a published PK-PD model used for neutropenia and leukocytopenia. Both of these two models adequately described the PK and PD of S-CKD602 and IHL-305.;Overall, this work helped to explain the nonlinear PK and high interpatient variability in PK of PEGylated liposomal anticancer agents and defined the role of the bi-directional interaction between PEGylated liposomes and the monocytes in the PK/PD of these agents.