Abstract 3700: Effect of gender on pharmacokinetic disposition of pegylated liposomal CKD-602 (S-CKD602) and optisomal topotecan (TLI) in rats

Introduction: S-CKD602 is a pegylated liposomal formulation of CKD-602, a camptothecin analogue. Optisomal Topotecan (TLI) is a sphingomyelin stabilized liposomal formulation of topotecan. The cytotoxicity of CKD-602, topotecan and other camptothecin analogues is related to the duration of exposure. Pegylated and sphingomyelin liposomal formulations have been designed to prolong drug circulation time, increase tumor delivery, and improve the therapeutic index. The pharmacokinetics (PK) of liposomal agents is highly variable in patients. Moreover, the factors associated with this variability are unknown. Thus, we evaluated the plasma PK disposition of TLI and S-CKD602 in male and female rats. Methods: TLI was administered at 0.93mg/kg IV x1 and S-CKD602 at 0.6 mg/kg IV x1 to male and female Sprague-Dawley rats via a bilateral jugular vein cannula. Plasma samples for TLI were obtained in 6 cohorts (n= 3 rats per cohort, total = 18 rats per gender): 1) pre, 1, and 3 min; 2) 5, 10, and 20 min; 3) 0.5, 1, and 2 h; 4) 4, 8, and 12 h; 5) 24, 36, and 48 h; 6) 60 and 72 h post dose. Plasma samples (n= 3 rats per time point per gender) for S-CKD602 were obtained prior to the end of the infusion, and at 4, 8, 24, 48, and 72 h after administration. Total (lactone and hydroxyl acid) form of sum total (encapsulated and released) CKD-602 and topotecan were measured via LC/MS. The clearance (CL) was estimated using noncompartmental PK analysis. Results: For TLI, the CL in male and female rats were 0.026 ± 0.0038 and 0.021 ± 0.0015 L/h/kg, respectively. For S-CKD602, the CL in male and female rats were 0.0037 ± 0.0004 and 0.0027 ± 0.0001 L/h/kg, respectively. For TLI and S-CKD602, CL was 1.2-fold (p=0.14) and 1.4-fold (p=0.009) lower in female rats compared with male rats, respectively. Conclusions: The CL of TLI and S-CKD602 was lower in female rats as compared with male rats. These studies suggest that gender may affect the disposition of liposomal formulations of drugs and may play a role in the high PK variability reported in patients treated with liposomal formulations of anticancer agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3700.