Evaluation of the relationship between patient factors and the reduction in clearance of pegylated liposomal doxorubicin

Abstract

2548 Background: The reticuloendothelial system (RES), which includes monocytes, may have a key role in clearance (CL) of nanoparticle sized pegylated liposomes. However, the factors affecting the CL of liposomes are unclear. Age, body composition, and monocyte count have been related to CL of liposomal agents (Zamboni, ASCO '07; Maruca, ASCO '07; Sidone, AACR- NCI-EORTC '07). The CL of pegylated liposomal doxorubicin (PLD) decreases significantly from cycle 1 to 3 (Gabizon, Cancer Chemother Pharmacol 2008). The objectives of this study were to evaluate factors associated with decreases in PLD CL. Methods: Patients (pts) with various solid tumors were randomized to PLD administered IV every 28 days at 30, 60 and 45 mg/m2 (n = 6) or 60, 30 and 45 mg/m2 (n = 6) on cycles 1, 2 and 3 respectively. Serial plasma samples for PLD pharmacokinetic (PK) analysis were obtained prior to and at 1 h, 24 h, 72 to 96 h, 7 d, 14 d, 21 d, and 28 d after PLD infusion on cycles 1, 2, and 3. Samples were processed to measure sum total (encapsulated + released) doxorubicin by HPLC with fluorescence. PLD CL was calculated by noncompartmental methods. Precycle monocyte count, age, and ratio of total body weight to ideal body weight were compared to PLD CL. Results: Mean + SD PLD CL on cycles 1 and 3 were 23.7 + 7.7 mL/h and 16.4 + 5.4 mL/h, (P < 0.0001). Pts with a reduction as compared with an increase in precycle monocyte count from cycle 1 to 3 had a mean + SD change in PLD CL of -11.5 + -3.5 mL/h and -5.3 + -3.0 mL/h, respectively (P = 0.09). Median age was 61 years old (yo). Pts > 61 yo and < 61 yo had a mean + SD change in PLD CL from cycles 1 to 3 of - 8.7 + -4.3 mL/h and -5.2 + -5.4 mL/h, respectively (P = 0.16). Conclusions: PLD CL decreased significantly from cycle 1 to 3. Decreased precycle monocyte count was associated with a larger decrease in PLD CL compared to increased monocyte count. Pts > 61 yo had a larger decrease in CL compared to pts < 61 yo. These results suggest monocytes are involved in the CL of PLD and that older pts may have less RES reserve and thus may be more likely to have a larger decrease in PLD CL with subsequent treatment cycles. Statistical significance was not met due to small sample size; however, further investigation of the association between changes in PLD CL and patient age and monocyte count is warranted. [Table: see text]