Technetium Tc 99m sulfur colloid phenotypic probe for the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin in women with ovarian cancer

Giovinazzo, Hugh; Kumar, Parag; Sheikh, Arif; Brooks, Kristina M; Ivanović, Marija; Walsh, Mark D.; Caron, Whitney P.; Kowalsky, Richard J.; Song, Gina; Whitlow, Ann; Clarke‐Pearson, Daniel L.; Brewster, Wendy R.; Le, Linda Van; Zamboni, Beth A.; Bae‐Jump, Victoria L.; Gehrig, Paola A.; Zamboni, William C.

doi:10.1007/s00280-015-2945-y

Cited by 20 publications

(9 citation statements)

References 29 publications

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“…Figure 1 and Table 2 show the results of the pharmacokinetic study for the 12 patients. The respective terminal elimination half-life ( T 1/2z ) of 188 Re-liposome in blood and plasma is 36.73 ± 14.00 h and 52.02 ± 45.21 h. Other clinical trials obtained similar results [41–44]. Golan et al [43], Chang et al [42], Harrington et al [41], and Giovinazzo et al [44] reported that the respective T 1/2 values for passive nano-targeted PEGylated liposomal mitomycin C prodrug, liposomal irinotecan, 111 In-DTPA-liposomes, and PEGylated liposomal doxorubicin are 18~27 h, 58~75 h, 79.6 h, and 40~100 h. The prolonged circulation and increased biological half-life of 188 Re-liposome allows the accumulation of Re-188 that is encapsulated in passive nano-targeted liposome in tumor sites because of EPR.…”

Section: Discussionsupporting

confidence: 55%

A phase 0 study of the pharmacokinetics, biodistribution, and dosimetry of 188Re-liposome in patients with metastatic tumors

et al. 2019

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Background Liposomes are drug nano-carriers that are capable of targeting therapeutics to tumor sites because of enhanced permeability retention (EPR). In several preclinical studies with various tumor-bearing mice models, 188 Re-liposome that has been developed by the Institute of Nuclear Energy Research (INER) demonstrates favorable in vivo tumor targeting, biodistribution, pharmacokinetics, and dosimetry. It inhibits the growth of tumors, increased survival, demonstrates good synergistic combination, and was safe to use. This study conducts a phase 0 low-radioactivity clinical trial of nano-targeted radiotherapeutics 188 Re-liposome to evaluate the effectiveness with which it targets tumors and the pharmacokinetics, biodistribution, dosimetry, and its safety in use. Twelve patients with metastatic cancers are studied in this trial. Serial whole-body scans and SPECT/CT are taken at 1, 4, 8, 24, 48, and 72 h after intravenous injection of 111 MBq of 188 Re-liposome. The effectiveness with which tumors are targeted, the pharmacokinetics, biodistribution, dosimetry, and safety are evaluated using the VelocityAI and OLINDA/EXM software. Blood samples are collected at different time points for a pharmacokinetics study and a safety evaluation that involves monitoring changes in liver, renal, and hematological functions. Results The T ½ z for 188 Re-liposome in blood and plasma are 36.73 ± 14.00 h and 52.02 ± 45.21 h, respectively. The doses of radiation that are absorbed to vital organs such as the liver, spleen, lung, kidney, and bone marrow are 0.92 ± 0.35, 1.38 ± 1.81, 0.58 ± 0.28, 0.32 ± 0.09, and 0.06 ± 0.01 mGy/MBq, respectively, which is far less than the reference maximum tolerance dose after injection of 188 Re-liposome. 188 Re-liposome is absorbed by metastatic tumor lesions and the normal reticuloendothelial (RES) system. Certain patients exhibit a therapeutic response. Conclusion This phase 0 exploratory IND study shows that nanocarrier 188 Re-liposome achieves favorable tumor accumulation and tumor to normal organ uptake ratios for a subset of cancer patients. The clinical pharmacokinetic, biodistribution, and dosimetry results justify a further dose-escalating phase 1 clinical trial. Trial registration Taiwan FDA MA1101G0 (Jan 31, 2012).

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Section: Discussionsupporting

confidence: 55%

A phase 0 study of the pharmacokinetics, biodistribution, and dosimetry of 188Re-liposome in patients with metastatic tumors

et al. 2019

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“…Another clinical example of the use of a companion diagnostic formulation for liposomal drugs is given in a study using 99m Tc-sulfur colloid (TSC) [309]. Palmar-plantar erythrodysesthesia (PPE) is a common side effect in patients treated with liposomal doxorubicin.…”

Section: Applications Of Radiolabelled Liposomesmentioning

confidence: 99%

Nuclear imaging of liposomal drug delivery systems: A critical review of radiolabelling methods and applications in nanomedicine

Man

Gawne

Rosales

2019

Advanced Drug Delivery Reviews

112

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The integration of nuclear imaging with nanomedicine is a powerful tool for efficient development and clinical translation of liposomal drug delivery systems. Furthermore, it may allow highly efficient imaging-guided personalised treatments. In this article, we critically review methods available for radiolabelling liposomes. We discuss the influence that the radiolabelling methods can have on their biodistribution and highlight the often-overlooked possibility of misinterpretation of results due to decomposition in vivo. We stress the need for knowing the biodistribution/pharmacokinetics of both the radiolabelled liposomal components and free radionuclides in order to confidently evaluate the images, as they often share excretion pathways with intact liposomes (e.g. phospholipids, metallic radionuclides) and even show significant tumour uptake by themselves (e.g. some radionuclides). Finally, we describe preclinical and clinical studies using radiolabelled liposomes and discuss their impact in supporting liposomal drug development and clinical translation in several diseases, including personalised nanomedicine approaches.

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“…This finding may be explained by a possible influence of concurrent carboplatin therapy on monocyte function and chemotaxis and subsequent alteration in the PK of PLD and other NPs, which would not have been measured by MPS function prior to drug administration [7,34]. …”

Section: Discussionmentioning

confidence: 99%

“…In all of the PK endpoints analyzed in the study, the relationship between serum hormone concentrations and PLD PK disposition appeared to be strongest in the 6 patients who received PLD monotherapy. This finding may be explained by a possible influence of concurrent carboplatin therapy on monocyte function and chemotaxis and subsequent alteration in the PK of PLD and other NPs, which would not have been measured by MPS function prior to drug administration [7,34].…”

Section: Discussionmentioning

confidence: 99%

Mononuclear phagocyte system function and nanoparticle pharmacology in obese and normal weight ovarian and endometrial cancer patients

Starling

Kumar

Lucas

et al. 2018

Cancer Chemother Pharmacol

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Purpose: Obesity may alter mononuclear phagocyte system (MPS) function and the pharmacology and efficacy of nanoparticles therapies, such as PEGylated liposomal doxorubicin (PLD). We aimed to evaluate relationships between hormone and chemokine mediators of MPS function and the pharmacokinetic (PK) exposure of PLD in obese and normal weight patients with ovarian and endometrial cancer. Methods: Hormone and chemokine mediators in obese and normal weight ovarian and endometrial cancer patients were measured. A separate pharmacology study was performed that evaluated the relationship between serum hormone concentrations, MPS function, and PK disposition of PLD in refractory ovarian cancer patients. Results: Univariate analysis revealed a significant relationship between serum estradiol and body mass index (OR: 8.64, 95% CI: 2.67–28.0, p<0.001). Estrone and testosterone concentrations were positively correlated with MPS function (rho=0.57 and 0.53, p=0.14 and 0.18, respectively) and inversely correlated with PLD PK exposure (rho= −0.75 and −0.76, respectively, p=0.02 for both). Conclusions: Higher MPS function resulting in reduced PLD exposure is a potential mechanism for reduced efficacy of PLD and other nanoparticles observed in obese patients with cancer. PK simulations suggest higher doses of PLD are required in obese patients to achieve similar exposures as standard dosing in normal weight patients.

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Technetium Tc 99m sulfur colloid phenotypic probe for the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin in women with ovarian cancer

Abstract: TSC is a phenotypic probe for PLD pharmacokinetics and pharmacodynamics and may be used to individualize PLD therapy in ovarian cancer and for other nanoparticles in development.

Cited by 20 publications

References 29 publications

A phase 0 study of the pharmacokinetics, biodistribution, and dosimetry of 188Re-liposome in patients with metastatic tumors

A phase 0 study of the pharmacokinetics, biodistribution, and dosimetry of 188Re-liposome in patients with metastatic tumors

Nuclear imaging of liposomal drug delivery systems: A critical review of radiolabelling methods and applications in nanomedicine

Mononuclear phagocyte system function and nanoparticle pharmacology in obese and normal weight ovarian and endometrial cancer patients

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