Bidirectional pharmacodynamic interaction between pegylated liposomal CKD-602 (S-CKD602) and monocytes in patients with refractory solid tumors.
BACKGROUND
STEALTH(®) liposomal CKD-602 (S-CKD602), a camptothecin analog, is eliminated by the reticuloendothelial system (RES), which consists of cells, including monocytes. We evaluated the relationship between monocyte and absolute neutrophil counts (ANCs) in the blood and pharmacokinetic disposition of S-CKD602 and nonliposomal CKD-602 (NL-CKD602) in patients.


METHODS
As part of a phase I study of S-CKD602 and phase I and II studies of NL-CKD602, the percent decreases in ANC and monocytes at their nadir were calculated. After S-CKD602, the amount of CKD-602 recovered in urine was measured.


RESULTS
For S-CKD602 in patients <60 years, the percent decrease in ANC and monocytes were 43  ±  31 and 58  ±  26%, respectively (P = 0.001). For S-CKD602 in patients ≥60, the percent decrease in ANC and monocytes were 41  ±  31 and 45  ±  36%, respectively (P =  0.50). For NL-CKD602 (n = 42), the percent decrease in ANC and monocytes were similar (P >  0.05). For S-CKD602, the relationship between the percent decrease in monocytes and CKD-602 recovered in urine was stronger in patients <60 (R(2) =  0.82), compared with patients ≥60 (R(2) =  0.30).


CONCLUSIONS
Monocytes are more sensitive to S-CKD602, compared with neutrophils, and the increased sensitivity is related to the liposomal formulation, not CKD-602. These results suggest that monocytes engulf S-CKD602, which causes the release of CKD-602 from the liposome and toxicity to the monocytes, and that the effects are more prominent in patients <60.
Zamboni
William C
WC
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA.
Maruca
Lauren J
LJ
Strychor
Sandra
S
Zamboni
Beth A
BA
Ramalingam
Suresh
S
Edwards
Robert P
RP
Kim
Jk
J
Bang
Yj
Y
Lee
Hy
H
Friedland
David M
DM
Stoller
Ronald G
RG
Belani
Chandra P
CP
Ramanathan
Ramesh K
RK
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine; D002452:Cell Count; D004351:Drug Resistance; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D012157:Mononuclear Phagocyte System / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000652:urine; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
D008081:Liposomes; D059004:Topoisomerase I Inhibitors; C116963:belotecan; D011092:Polyethylene Glycols; D002166:Camptothecin