Abstract C127: Factors affecting the pharmacokinetics (PK) and pharmacodynamics (PD) of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors

Abstract

Abstract Background: Irinotecan (CPT-11) is a prodrug of SN-38 that has antitumor activity in a wide range of solid tumors. IHL-305 is a PEGylated-liposomal formulation of CPT-11. The PK of liposomal agents is highly complex due to the variability in the disposition of the inactive-encapsulated drug and the release of active-drug from the liposome. We previously reported that age, body weight, and monocytes affect the PK and PD of PEGylated liposomal agents. Thus, we evaluated the effect of these factors on the PK and PD of IHL-305 as part of a phase I study. Methods: IHL-305 was administered IV over 1 h at 3.5, 7, 10.5, 14, 28, 33.5, 37, 50, 67, 80, 88, 120, 160, and 210 mg/m2 q 28 d. Serial plasma samples were obtained prior to infusion, at the end of infusion (EOI), and from 1 to 192 h after EOI. Plasma samples were processed to measure sum total (encapsulated + released) CPT-11, released CPT-11, SN-38 and SN-38 glucuronide (SN-38G). The total (lactone + hydroxy acid) forms were measured by HPLC. The area under the plasma concentration versus time curve (AUC) for each form was calculated from 0 to last sampling time and from 0 to ∞. The ratio of total body weight to ideal body weight (TBW/IBW) was calculated. Results: 39 patients (pts) (13 male) were treated. Median (range) of age and TBW/IBW were 60 years old (yo) (42–75 yo) and 1.16 (0.81–2.7), respectively. There was high inter-patient variability in the PK disposition of sum total CPT-11, released CPT-11, SN-38 and SN-38G. Sum total CPT-11 is associated with linear and non-linear clearance. The ratio of SN-38 to released CPT-11 and SN-38G to SN-38 were similar to those reported after irinotecan. Pts whose age and TBW/IBW were greater than the median of the study had a 1.7- to 2.6-fold higher ratio of released CPT-11 AUC to sum total CPT-11 AUC. In pts < 60 yo and in pts ≥ 60 yo, the ratio of % decrease in monocytes at nadir to % decrease in ANC at nadir were 1.65 ± 1.36 and 1.24 ± 0.68, respectively. There was an inverse relationship between pts age and % decrease in monocytes at nadir with younger pts having a higher % decrease in monocytes. Pts with a higher % decrease in monocytes at nadir have an increased clearance of sum total CPT-11 and increased exposure of released CPT-11 and ratio of released CPT-11 AUC to sum total CPT-11 AUC. Conclusions: PK and PD of IHL-305 are consistent with a PEGylated-liposomal carrier. IHL-305 has pharmacological advantages compared with irinotecan. The inter-patient variability in the PK and PD of IHL-305 was associated with age, body composition, and monocytes. Sponsored by Yakult Honsha Co., Ltd., Tokyo, Japan Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C127.