Bidirectional pharmacodynamic interaction between pegylated liposomal CKD-602 (S-CKD602) and monocytes in patients with refractory solid tumors

Zamboni, William C.; Maruca, Lauren; Strychor, Sandra; Zamboni, Beth A.; Ramalingam, Suresh S.; Edwards, Robert P.; Kim, J. K.; Bang, Yung‐Jue; Lee, H. Y.; Friedland, David; Stoller, Ronald G.; Belani, Chandra P.; Ramanathan, Ramesh K.

doi:10.3109/08982104.2010.496085

Cited by 44 publications

(57 citation statements)

References 17 publications

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“…18,19 However, the monocytopenia is greater and occurs earlier after administration of liposomal agents compared with nonliposomal agents. 2,16 The results of our prior study suggest that monocytes are more sensitive to S-CKD602 as compared with neutrophils, and that this increased sensitivity is related to the liposomal formulation and not the encapsulated CKD-602. 16 Therefore, the monocytopenia following administration of PEGylated liposomal agents may have a different mechanism from monocytopenia following treatment with conventional small-molecule chemotherapeutic drugs.…”

Section: Introductionmentioning

confidence: 98%

“…2,16 The results of our prior study suggest that monocytes are more sensitive to S-CKD602 as compared with neutrophils, and that this increased sensitivity is related to the liposomal formulation and not the encapsulated CKD-602. 16 Therefore, the monocytopenia following administration of PEGylated liposomal agents may have a different mechanism from monocytopenia following treatment with conventional small-molecule chemotherapeutic drugs. Incorporation of the bidirectional interaction between PEGylated liposomal formulation and monocytes is important to the characterization of this novel PK and PD of these agents.…”

Section: Introductionmentioning

confidence: 98%

“…16 A mechanismbased model based on receptor binding kinetics was developed to describe the bidirectional interaction between the concentration versus time profile of encapsulated CKD-602, and the time course of monocytes. A myelosuppressionbased model, in absence of the bidirectional interaction, was also developed to compare with the mechanism-based model.…”

Section: Model Developmentmentioning

confidence: 99%

“…17 As monocytes of the MPS play an important role in the PK disposition of liposomes, monocytopenia after administration of PEGylated liposomal anticancer agents was selected as a PD measure of these agents. 2,16 Monocytopenia is also commonly observed after small-molecule chemotherapy, as a result of myelosuppression. 18,19 However, the monocytopenia is greater and occurs earlier after administration of liposomal agents compared with nonliposomal agents.…”

Section: Introductionmentioning

confidence: 99%

“…15,16 Uptake of the liposomes, or nanoparticles, by the MPS usually results in sequestering of the encapsulated drug in the MPS. The sequestered drug in the MPS may cause acute and/or long-term cytotoxicity to the MPS.…”

Section: Introductionmentioning

confidence: 99%

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

Wu¹,

Ramanathan²,

Zamboni³

et al. 2012

IJN

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S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional pharmacokinetic-pharmacodynamic (PK-PD) interaction between S-CKD602 and monocytes. Plasma concentrations of encapsulated CKD-602 and monocytes counts from 45 patients with solid tumors were collected following intravenous administration of S-CKD602 in the phase I study. The PK-PD models were developed and fit simultaneously to the PK-PD data, using NONMEM ® . The monocytopenia after administration of S-CKD602 was described by direct toxicity to monocytes in a mechanism-based model, and by direct toxicity to progenitor cells in bone marrow in a myelosuppression-based model. The nonlinear PK disposition of S-CKD602 was described by linear degradation and irreversible binding to monocytes in the mechanismbased model, and Michaelis-Menten kinetics in the myelosuppression-based model. The mechanism-based PK-PD model characterized the nonlinear PK disposition, and the bidirectional PK-PD interaction between S-CKD602 and monocytes.

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

Section: Model Developmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Wu¹,

Ramanathan²,

Zamboni³

et al. 2012

IJN

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Translation to the Clinic: Preclinical and Clinical Pharmacology Studies of Nanoparticles – The Translational Challenge

Tyson

Osae

Madden

et al. 2016

Pharmaceutical Nanotechnology: Innovation and Production

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Challenges in preclinical to clinical translation for anticancer carrier‐mediated agents

Lucas

Madden

Zamboni

2016

WIREs Nanomed Nanobiotechnol

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Major advances in carrier-mediated agents (CMAs), which include nanoparticles and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages over their small-molecule counterparts, there is substantial variability in how individual CMA formulations and patient characteristics affect the pharmacology, pharmacokinetics (PK), and pharmacodynamics (PD) (efficacy and toxicity) of these agents. Development or selection of animal models is used to predict the effects within a particular human disease. A breadth of studies have begun to emphasize the importance of preclinical animal models in understanding and evaluating the interaction between CMAs and the immune system and tumor matrix, which ultimately influences CMA PK (clearance and distribution) and PD (efficacy and toxicity). It is fundamental to study representative preclinical tumor models that recapitulate patients with diseases (e.g., cancer) and evaluate the interplay between CMAs and the immune system, including the mononuclear phagocyte system (MPS), chemokines, hormones, and other immune modulators. Furthermore, standard allometric scaling using body weight does not accurately predict drug clearance in humans. Future studies are warranted to better understand the complex pharmacology and interaction of CMA carriers within individual preclinical models and their biological systems, such as the MPS and tumor microenvironment, and their application to allometric scaling across species. WIREs Nanomed Nanobiotechnol 2016, 8:642-653. doi: 10.1002/wnan.1394 For further resources related to this article, please visit the WIREs website.

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Bidirectional pharmacodynamic interaction between pegylated liposomal CKD-602 (S-CKD602) and monocytes in patients with refractory solid tumors

Cited by 44 publications

References 17 publications

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

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

Translation to the Clinic: Preclinical and Clinical Pharmacology Studies of Nanoparticles – The Translational Challenge

Challenges in preclinical to clinical translation for anticancer carrier‐mediated agents

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