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

Wu, Huali; Ramanathan, Ramesh K.; Zamboni, Beth A.; Strychor, Sandra; Ramalingam, Suresh S.; Edwards, Robert P.; Friedland, David; Stoller, Ronald G.; Belani, Chandra P.; Maruca, Lauren; Bang, Yung Jue; Zamboni, William C.

doi:10.2147/ijn.s35751

Cited by 8 publications

(7 citation statements)

References 36 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, dose reductions may be needed in subsequent cycles to minimize the risk of toxicity. These results and prior results reporting a relationship between the reduction in monocyte counts in blood and the clearance of PEGylated liposomal agents in patients where greater monocyte reductions were associated with greater clearance of the liposomal agents suggest that there is a bidirectional interaction between NPs and the MPS, where the MPS cells take up NPs and the NPs have pharmacologic and/or toxicologic effects on the MPS cells (72,73). Interestingly, repeat dose studies of PEGylated liposomal doxorubicin in mice and rats did not report accumulation of drug in plasma suggesting that these preclinical models may not accurately reflect the disposition of PEGylated liposomal agents after repeated dosing (74,75).…”

Section: Introduction: Safety and Toxicological Effects: A Jacobssupporting

confidence: 74%

Summary Report of PQRI Workshop on Nanomaterial in Drug Products: Current Experience and Management of Potential Risks

Bartlett

Brewster

Brown

et al. 2014

AAPS J

Self Cite

View full text Add to dashboard Cite

At the Product Quality Research Institute (PQRI) Workshop held last January 14-15, 2014, participants from academia, industry, and governmental agencies involved in the development and regulation of nanomedicines discussed the current state of characterization, formulation development, manufacturing, and nonclinical safety evaluation of nanomaterial-containing drug products for human use. The workshop discussions identified areas where additional understanding of material attributes, absorption, biodistribution, cellular and tissue uptake, and disposition of nanosized particles would continue to inform their safe use in drug products. Analytical techniques and methods used for in vitro characterization and stability testing of formulations containing nanomaterials were discussed, along with their advantages and limitations. Areas where additional regulatory guidance and material characterization standards would help in the development and approval of nanomedicines were explored. Representatives from the US Food and Drug Administration (USFDA), Health Canada, and European Medicines Agency (EMA) presented information about the diversity of nanomaterials in approved and newly developed drug products. USFDA, Health Canada, and EMA regulators discussed the applicability of current regulatory policies in presentations and open discussion. Information contained in several of the recent EMA reflection papers was discussed in detail, along with their scope and intent to enhance scientific understanding about disposition, efficacy, and safety of nanomaterials introduced in vivo and regulatory requirements for testing and market authorization. Opportunities for interaction with regulatory agencies during the lifecycle of nanomedicines were also addressed at the meeting. This is a summary of the workshop presentations and discussions, including considerations for future regulatory guidance on drug products containing nanomaterials.

show abstract

Section: Introduction: Safety and Toxicological Effects: A Jacobssupporting

confidence: 74%

Summary Report of PQRI Workshop on Nanomaterial in Drug Products: Current Experience and Management of Potential Risks

Bartlett

Brewster

Brown

et al. 2014

AAPS J

Self Cite

View full text Add to dashboard Cite

show abstract

“…[18][19][20] We have also reported that monocytes are more sensitive to S-CKD602 compared with neutrophils, and the increased sensitivity is related to the liposomal formulation and not CKD-602. 21,22 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 aged ,60 years. 20,22,23 We were also the first group to report that body composition alters the pharmacokinetics of PEGylated liposomal agents in mice and in patients.…”

mentioning

confidence: 88%

“…Pharmacokinetic model parameters for sum total CPT-11 after administration of IHL-305 included the volume of the central compartment (V c ) and intercompartment rate constants, (k 12 , k 21 ). 29 The elimination rate constant from the central compartment (k 10 ) was used to represent linear clearance.…”

Section: Compartmental Pharmacokinetic Analysismentioning

confidence: 99%

Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors

Wu¹,

Infante

Keedy³

et al. 2015

IJN

Self Cite

View full text Add to dashboard Cite

IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged <60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years. There was an inverse relationship between patient age and percent decrease in monocytes at nadir, ie, younger patients have a higher percent decrease in monocytes. Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11. The pharmacokinetics and pharmacodynamics of IHL-305 are consistent with those of other PEGylated liposomal carriers. Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes.

show abstract

“…Taxanes are known to interact with tumor-associated macrophage and circulating monocytes and cause leukopenia [35]. It is also known that circulating monocytes regenerate every 2-3wk, are recruited into the tumor compartment from the circulation, where they differentiate into macrophage [36].…”

Section: Discussionmentioning

confidence: 99%

Targeting of metastasis-promoting tumor-associated fibroblasts and modulation of pancreatic tumor-associated stroma with a carboxymethylcellulose-docetaxel nanoparticle

Ernsting

Hoang

Lohse

et al. 2015

Journal of Controlled Release

110

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinomas are characterized by the desmoplastic reaction, a dense fibrous stroma that has been shown to be supportive of tumor cell growth, invasion, and metastasis, and has been associated with resistance to chemotherapy and reduced patient survival. Here, we investigated targeted depletion of stroma for pancreatic cancer therapy via taxane nanoparticles. Cellax-DTX polymer is a conjugate of docetaxel (DTX), polyethylene glycol (PEG), and acetylated carboxymethylcellulose, a construct which condenses into well-defined 120nm particles in aqueous solution, and is suitable for intravenous injection. We examined Cellax-DTX treatment effects in highly stromal primary patient-derived pancreatic cancer xenografts and in a metastatic PAN02 mouse model of pancreatic cancer, focussing on specific cellular interactions in the stroma, pancreatic tumor growth and metastasis. Greater than 90% of Cellax-DTX particles accumulate in smooth muscle actin (SMA) positive cancer-associated fibroblasts which results in long-term depletion of this stromal cell population, an effect not observed with Nab-paclitaxel (Nab-PTX). The reduction in stromal density leads to a >10-fold increase in tumor perfusion, reduced tumor weight and a reduction in metastasis. Consentingly, Cellax-DTX treatment increased survival when compared to treatment with gemcitabine or Nab-PTX in a metastatic PAN02 mouse model. Cellax-DTX nanoparticles interact with the tumor-associated stroma, selectively interacting with and depleting SMA positive cells and macrophage, effects which are associated with significant changes in tumor progression and metastasis.

show abstract

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

Cited by 8 publications

References 36 publications

Summary Report of PQRI Workshop on Nanomaterial in Drug Products: Current Experience and Management of Potential Risks

Summary Report of PQRI Workshop on Nanomaterial in Drug Products: Current Experience and Management of Potential Risks

Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors

Targeting of metastasis-promoting tumor-associated fibroblasts and modulation of pancreatic tumor-associated stroma with a carboxymethylcellulose-docetaxel nanoparticle

Contact Info

Product

Resources

About