Plasma, tumor, and tissue disposition of STEALTH liposomal CKD-602 (S-CKD602) and nonliposomal CKD-602 in mice bearing A375 human melanoma xenografts.
OBJECTIVE
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).


METHODS
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 chromatography-mass 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 >1 ng/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.h, respectively. The duration of time the CKD-602 concentration was >1 ng/mL in tumor ECF after S-CKD602 and nonliposomal CKD-602 was >72 and approximately 20 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.


CONCLUSIONS
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.
Zamboni
William C
WC
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. zamboniwc@msx.upmc.edu
Strychor
Sandra
S
Joseph
Erin
E
Walsh
Dustin R
DR
Zamboni
Beth A
BA
Parise
Robert A
RA
Tonda
Margaret E
ME
Yu
Ning Y
NY
Engbers
Charles
C
Eiseman
Julie L
JL
D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008545:Melanoma / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D017551:Microdialysis / Q000379:methods; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
D008081:Liposomes; C116963:belotecan; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D002166:Camptothecin