Plasma, Tumor, and Tissue Disposition of STEALTH Liposomal CKD-602 (S-CKD602) and Nonliposomal CKD-602 in Mice Bearing A375 Human Melanoma Xenografts

Abstract

Purpose: S-CKD602 is a STEALTH liposomal formulation of CKD-602, a camptothecin analogue. The cytotoxicity of camptothecin analogues is related to the duration of exposure in the tumor. STEALTH liposomal formulations contain lipid conjugated to methoxypolyethylene glycol and have been designed to prolong drug circulation time, increase tumor delivery, and improve the therapeutic index. For STEALTH liposomal formulations of anticancer agents to achieve antitumor effects, the active drug must be released into the tumor extracellular fluid (ECF). Experimental Design: S-CKD602 at 1 mg/kg or nonliposomal CKD-602 at 30 mg/kg was administered once via tail vein to mice bearing A375 human melanoma xenografts. Mice (n = 3 per time point) were euthanized at 0.083 to 24 h, 48 h, and 72 h after S-CKD02 and from 0.083 to 24 h after nonliposomal CKD-602. Plasma samples were processed to measure encapsulated, released, and sum total (encapsulated plus released) CKD-602, and tumor and tissue samples were processed to measure sum total CKD-602. Microdialysis samples of tumor ECF were obtained from 0 to 2 h, 4 to 7 h, and 20 to 24 h after nonliposomal CKD-602 and from 0 to 2 h, 24 to 27 h, 48 to 51 h, and 72 to 75 h after S-CKD602. A liquid chromatographymass spectrometry assay was used to measure the total (sum of lactone and hydroxyl acid) CKD-602. The area under the concentration-versus-time curves (AUC) from 0 to infinity and time >1ng/mL in tumor were estimated.Results: For S-CKD602, the CKD-602 sum total AUC in plasma and tumor and the CKD-602 AUC in tumor ECF were 201,929, 13,194, and 187 ng/mL h, respectively. For S-CKD602, 82% of CKD-602 remains encapsulated in plasma. For nonliposomal CKD-602, the CKD-602 AUC in plasma and tumor and the CKD-602 AUC in tumor ECF were 9,117, 11,661, and 639 ng/mL Á h, respectively. The duration of time the CKD-602 concentration was >1ng/mL in tumor ECF after S-CKD602 and nonliposomal CKD-602 was >72 and f20 h, respectively. For S-CKD602, the CKD-602 sum total exposure was 1.3-fold higher in fat as compared with muscle. The ratio of CKD-602 sum total exposure in fat to muscle was 3.8-fold higher after administration of S-CKD602 compared with nonliposomal CKD-602. Conclusion: S-CKD602 provides pharmacokinetic advantages in plasma, tumor, and tumor ECF compared with nonliposomal CKD-602 at 1/30th of the dose, which is consistent with the improved antitumor efficacy of S-CKD602 in preclinical studies. The distribution of S-CKD602 is greater in fat compared with muscle whereas the distribution of nonliposomal CKD-602 is greater in muscle compared with fat.These results suggest that the body composition of a patient may affect the disposition of S-CKD602 and released CKD-602.

Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients

“…Total (lactone + hydroxyl acid) concentrations of encapsulated and released CKD-602 in plasma were determined by liquid chromatography-tandem mass spectrometry. 1 The lower limit of quantitation of the total form of encapsulated and released CKD-602 were 2 ng/mL and 0.05 ng/mL, respectively. Samples of peripheral blood were collected before dosing on days 7, 14, 21, and 28 and used to measure monocyte counts.…”

“…CKD-602 is a novel camptothecin analog which inhibits topoisomerase I. [1][2][3] Nonliposomal CKD-602 administered intravenously (IV) at 0.5 mg/m 2 /day for five consecutive days every 3 weeks has been approved in Korea for the treatment of small cell lung cancer, and relapsed ovarian cancer. [4][5][6][7] S-CKD602 STEALTH ® liposomes are composed of the lipids distearoylphosphatidylcholine and distearoylphosphatidylethanolamine, covalently bound to N-(carbonylmethoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3 phosphoethanolamine sodium salt (DSPE-MPEG-2000).…”

“…In this formulation, CKD-602 lactone is encapsulated in the aqueous core of the liposome with an encapsulation efficiency of .85%. 1,8 Encapsulation of the CKD-602 in the acidic core of a PEGylated liposome protects the biologically active lactone form of the drug from being converted to the inactive hydroxyacid form in the blood. The liposomal encapsulation also allows release of the active-lactone form into the tumor over a prolonged period of time, which is ideal for a cell-cycle-specific drug.…”

Efficacy and Pharmacokinetics of a Modified acid-labile docetaxel-PRINT ® Nanoparticle Formulation Against non-small-cell Lung Cancer Brain Metastases

“…As brain metastasis recurrence is common among patients with advanced NSCLC, optimizing the passage of anticancer agents across the blood-brain barrier, increasing chemotherapeutic concentrations in intracranial and extracranial tumors and decreasing systemic toxicities are important considerations to improve treatment of this disease. Newer delivery techniques, like nanoparticles and carrier-mediated technologies, have illustrated these advantages in the setting of intracranial cancer [6][7][8][9][10]. Clinically, activity of nanoparticle-based systemic therapy has been illustrated in the setting of breast cancer brain metastases, another solid tumor type where brain metastasis recurrence is common [11].…”

“…While several studies have shown the superiority of nanoparticle anticancer agents in intracranial malignancies over standard formulations, the mechanism underlying this observation has yet to be fully elucidated [6][7][8][9][10][11][12]. The working hypothesis has been that prolonged exposure to anticancer agents afforded by nanoparticle technology may increase passage of small molecules across the 'blood tumor barrier,' a barrier potentially compromised by the presence of tumor [12].…”