Major advances in the field of carrier-mediated agents (CMAs) have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages over their small-molecule counterparts (solubility,duration of exposure, and delivery to the site of action are higher), these agents display substantial variability in systemic clearance (CL) and distribution, tumor delivery, and pharmacologic effects. This review provides an overview of factors that affect the pharmacokinetics (PK) and pharmacodynamics (PD) of CMAs in preclinical models and patients.

S-CKD602 is a pegylated liposomal formulation of CKD-602. This study is the first to evaluate the factors affecting the high interpatient variability in the pharmacokinetic disposition of S-CKD602. S-CKD602 was administered intravenously (i.v.) every 3 weeks as part of a phase I study. Pharmacokinetics studies of the liposomal encapsulated and released CKD-602 in plasma were performed. The pharmacokinetic variability of S-CKD602 is associated with both linear and nonlinear clearances. Patients > or =60 years of age have a 2.7-fold higher exposure of S-CKD602 as compared with patients <60 years of age (P = 0.02). Patients with a lean body composition have a higher plasma exposure of S-CKD602 (P = 0.02). Patients who have received prior therapy with pegylated liposomal doxorubicin (PLD) have a 2.2-fold higher exposure of S-CKD602 as compared with patients who have not received PLD (P = 0.045). Prolonged exposure of the encapsulated drug in plasma over 1-2 weeks provides significant pharmacologic advantages. The high interpatient variability in the pharmacokinetic disposition of S-CKD602 was associated with age, body composition, saturable clearance, and prior PLD therapy.

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